CN203870015U - On-line concentration detection device for active pharmaceutical ingredient in cooling crystallization process - Google Patents
On-line concentration detection device for active pharmaceutical ingredient in cooling crystallization process Download PDFInfo
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- CN203870015U CN203870015U CN201420018040.4U CN201420018040U CN203870015U CN 203870015 U CN203870015 U CN 203870015U CN 201420018040 U CN201420018040 U CN 201420018040U CN 203870015 U CN203870015 U CN 203870015U
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- 238000001514 detection method Methods 0.000 title claims abstract description 80
- 238000002425 crystallisation Methods 0.000 title claims abstract description 65
- 238000000034 method Methods 0.000 title claims abstract description 64
- 230000008025 crystallization Effects 0.000 title claims abstract description 50
- 238000001816 cooling Methods 0.000 title claims abstract description 17
- 239000008186 active pharmaceutical agent Substances 0.000 title abstract 3
- 239000000523 sample Substances 0.000 claims abstract description 29
- 238000004891 communication Methods 0.000 claims abstract description 19
- 239000000835 fiber Substances 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 13
- 238000005102 attenuated total reflection Methods 0.000 abstract description 5
- 238000009529 body temperature measurement Methods 0.000 abstract 3
- 239000000243 solution Substances 0.000 description 83
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 20
- 238000002211 ultraviolet spectrum Methods 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 14
- 238000002835 absorbance Methods 0.000 description 12
- 230000000875 corresponding effect Effects 0.000 description 11
- 238000005259 measurement Methods 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 8
- 229960005489 paracetamol Drugs 0.000 description 8
- 238000012549 training Methods 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 5
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- -1 Metagin ester Chemical class 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
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- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 229910002056 binary alloy Inorganic materials 0.000 description 1
- 239000004566 building material Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001739 density measurement Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000012625 in-situ measurement Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
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- 230000002277 temperature effect Effects 0.000 description 1
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- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
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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
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/55—Specular reflectivity
- G01N21/552—Attenuated total reflection
-
- 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
- G01N21/8507—Probe photometers, i.e. with optical measuring part dipped into fluid sample
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- Investigating Or Analysing Materials By Optical Means (AREA)
Abstract
The utility model discloses an on-line concentration detection device for an active pharmaceutical ingredient in a cooling crystallization process. The device comprises a crystallization kettle, a constant-temperature tank, a UV-vis fiber optic spectrometer provided with an ATR (attenuated total reflectance) detection probe, a temperature measurement thermal resistor, a stirrer, a data communication converter and a control computer, wherein the UV-vis fiber optic spectrometer provided with the ATR detection probe, the temperature measurement thermal resistor and the stirrer are directly mounted in the crystallization kettle which is connected with the constant temperature tank; and the constant temperature tank, the UV-vis fiber optic spectrometer provided with the ATR detection probe, the temperature measurement thermal resistor and the stirrer are connected with the control computer through the data communication converter. The on-line concentration detection device realizes the fast on-line detection of the concentration of the active pharmaceutical ingredient, has the advantages of large applicable temperature range, high detection accuracy, good repeatability and simplicity in operation, and is applicable to popularization of on-line concentration detection of the crystallization process.
Description
Technical field
The utility model relates to a kind of online concentration and detects, particularly relate to a kind of based on ATR ?the online concentration detection apparatus of crystallisation by cooling process medicine activity component of UV technology, belong to online measuring technique field.
Background technology
Crystallization, as a kind of chemical separating and purifier units operation of high-efficiency environment friendly energy-conservation, is widely used in the production run of the products such as medicine, food, chemical fertilizer, chemical reagent, catalyzer, spices, vitamin, building materials.In recent years, along with the demand growth of high added value fine chemical product, specialty chemicals and specific crystal formation medicine, how more effectively to supervise, regulate and control crystallization process and become gradually academia and industry member study hotspot and difficult point.Degree of supersaturation is that in crystallization process, nucleus forms and the fundamental driving force of crystal growth, and the quality of crystalline product is had to appreciable impact.Degree of supersaturation is under uniform temperature, pressure, and in solution, the concentration of solute has exceeded the part of the solubleness of solute under this temperature, pressure.Therefore, the detection of concentration and control most importantly in crystallization process, is the key factor of product quality control.
Common solution concentration detection method has gravimetric method, densimetry, electrical conductivity method etc.
Gravimetric method is solution concentration measuring method the most intuitively.The method is weighed the solution example of extraction, by the dry solvent of removing, measures dried solute quality, calculates the solvent quality of evaporation, finally calculates the concentration of solution.But the method requires not contain crystal grain in sample, be difficult to again complete desolvation, and hand sampling wait is of a specified duration proving time, so method is unsuitable for on-line measurement.
Between the density of most of binary systems and its concentration, have corresponding funtcional relationship, the density measure of solution can obtain concentration information indirectly.But the same with solution concentration, density is not the physical quantity that can directly measure, belongs to double measurement.Enter bubble and the small grains that in densitometric solution, may contain, the subtle change of measuring cell temperature etc. all can exert an influence to density measurements.
Conductivity is the function of solution concentration and temperature, therefore the measurement of conductivity can realize the online detection of solution concentration.But electrical conductivity method is not suitable for the measurement of organic system conventionally, scale formation in conductivity measurement pond, can cause the huge measuring error of conductivity, and then affects the accuracy that solution concentration is measured; Its measurement result is vulnerable to temperature, relative substance disturbing effect, and the existence of the problems referred to above has limited its application in the on-line measurement of crystallization process concentration.
Chinese utility model patent application CN101788464A adopts UV spectrum to carry out online concentration detection, but need to be by solution by micro-strainer filtering particle, and filtrate is delivered to after detection cell detects and returned to crystallization kettle.Though this kind of method realized online detection, do not realize original position Real-Time Monitoring, is only applicable to dilution crystallization process, and process, system complex, not directly easy.
Utility model content
To be solved in the utility model is prior art length detection time, repetition stability and the poor problem of agility easy to detect, provide a kind of convenient and swift, stable accurately for the online device detecting of crystallisation by cooling process medicine activity component concentration, realize real-time online and detect crystallization process solution concentration.
ATR ?UV be attenuated total reflection ultraviolet spectrum, the detecting layer of Technique of Attenuated Total Reflectance is extremely low, can effectively avoid in crystallization solution because particle exists the light scattering causing, thereby effectively overcome traditional ultraviolet spectrum and cannot in the solution that has particle, carry out the shortcoming of Measurement and analysis.Therefore, ATR ?UV spectrum in testing process without to pre-service such as solution filter, can directly adopt probe to carry out in site measurement, accurately true reflection concentration information.Its principle of work is as follows: the light signal that single-core fiber transmits, by arriving detector after a fixed grating dispersion, between the light signal (absorbance) detecting and the concentration of solution, can set up relation one to one.
The utility model object is achieved through the following technical solutions:
Based on ATR ?the online concentration detection apparatus of crystallisation by cooling process medicine activity component of UV, comprise crystallization kettle, calibration cell, with the UV of ATR detection probe ?vis fiber spectrometer, thermometric thermal resistance, stirrer, data communication converter and control computer; With the UV of ATR detection probe ?vis spectrometer, thermometric thermal resistance and stirrer be directly installed in crystallization kettle; Crystallization kettle is connected with calibration cell; Calibration cell, with the UV of ATR detection probe ?vis spectrometer, thermometric thermal resistance and stirrer by data communication converter with control computer and be connected.
The utility model ATR detection probe directly immerse in the slurry of crystallization kettle, obtain ATR ?UV spectrum, without filtering particle, in site measurement.Solution temperature is recorded in real time by thermometric thermal resistance, and is sent to control computer by data communication converter (AD/DA).Visual Studio programming realizes solution concentration and automatically measures calculatings, man-machine interaction interface and show in real time and the preservation of back-end data record.
In medicine activity component crystallization process, the medicine activity component that solution dissolves ultraviolet region setted wavelength 200 ?have stronger absorption, the measure of the change solution concentration that can utilize ultraviolet region setted wavelength to absorb within the scope of 400nm.Quantitative relationship between light absorption situation and current material concentration adopt Lambert ?Beer law describe, its primary expression form is R=kyl, in formula, R is absorbance, k is absorptivity, y is solute concentration, l is light path.The utility model adopt with the UV of ATR detection probe ?vis fiber spectrometer Real-time Obtaining ATR ?UV spectrum, change of component and the concentration change of solution in real-time in-situ feedback crystallization process solution.
In the utility model, ATR ?UV spectrum change its absorption peak with solute concentration and have to a certain degree skew, with concentration solution along with its absorption peak of eustasy of temperature not have to have to a certain degree eustasy under the prerequisite being offset yet.For overcoming the above-mentioned peak skew existing in measurement of concetration, the utility model is got the absorbance at multi-wavelength place and is carried out modeling in spectral absorption peak, and solution temperature is associated with to concentration prediction model, the peak skew causing to eliminate concentration effect and temperature effect.On this basis, adopt partial least square method to carry out independent variable (temperature T, absorbance R) decomposition and the extraction of information, effectively eliminate multicollinearity between variable, carry out stoichiometry Multivariate Correction and obtain the relevant correlation coefficient of concentration detection model, the utility model application concentration detection model is as follows:
In formula, y is solution concentration (g solute/g solvent), R be ATR ?UV spectral absorbance value, T be solution temperature (DEG C), a, b and c are correlation coefficient.After concentration calibration completes, solution concentration y is that objective function is dependent variable, and the absorbance R and the spectra collection corresponding temperature T that choose some wavelength place are independent variable, returns and obtains correlation coefficient a, b and c by partial least square method.By the spectrum of crystallization process Real-time Obtaining and the above-mentioned detection model of temperature information substitution, can automatically calculate acquisition corresponding concentration by controlling computer, realize crystallization process solution concentration and detect online.
Return concentration detection model in partial least square method
in when relevant correlation coefficient, adopt data processing software SIMCA to carry out data regression, using solution concentration y as dependent variable, ATR ?UV spectrum and temperature data carry out partial least square method data regression as independent variable.In regression process, random selected part data are as training set, and remainder data is as checksum set, and training set is used for setting up preliminary concentration detection model, and checksum set is used for the ability such as prediction of assessment models, and then adjusts, obtains optimum correlation coefficient.
In the utility model, corresponding to temperature T
0when (a certain temperature spot of medicine activity component crystallization process), if institute's obtain solution concentration is that solute is at T
0time saturation solubility, before crystallization, temperature is T
0± 15 DEG C of variation ranges, evenly get 5 ?10 temperature spots ATR ?UV spectral value.
Compared with prior art, tool has the following advantages the utility model:
1) the utility model is got the original spectrum under multiple temperature conditions, and be directly used in partial least square method and return and obtain detection model, simple and fast, and can effectively eliminate the impact of the peak skew that temperature, concentration cause.
2) the utility model ATR ?UV probe directly immerse in slurry, without filtering particle, realize real-time in-situ measurement.
3) the utility model Applicable temperature variation range is large, accuracy is high, favorable reproducibility, is not subject to external environmental condition impact.
4) the utility model UV fiber spectrometer in conjunction with ATR ?cost and the maintenance cost of UV probe low, the online concentration that this technology is applicable to China's crystallization industrial process detects.
5) special purpose device under the utility model, simple for structure, dexterous practical, applicability is wide.
6) on-line measuring device and method that the solution concentration original position that the utility model provides in real time, Applicable temperature scope is large, accuracy of detection is high, reproducible, simple to operate, be with a wide range of applications.
Brief description of the drawings
Fig. 1 is online concentration detection apparatus structural representation described in the utility model;
Fig. 2 is that online the detection with gravimetric method of embodiment 1 solution concentration analyzed numerical result comparison diagram.
Embodiment
For understanding better the utility model, further the utility model is described below in conjunction with drawings and Examples, but embodiment of the present utility model is not limit so.
As shown in Figure 1, based on ATR ?the online concentration detection apparatus of crystallisation by cooling process medicine activity component of UV, comprise crystallization kettle 1, calibration cell 2, with the UV of ATR detection probe ?vis fiber spectrometer 3, thermometric thermal resistance 4, stirrer 5, data communication converter (AD/DA) 6 and control computer 7; With the UV of ATR detection probe ?vis spectrometer 3, thermometric thermal resistance 4 and stirrer 5 be directly installed in crystallization kettle 1; Crystallization kettle 1 is connected with calibration cell 2; Calibration cell 2, with the UV of ATR detection probe ?vis spectrometer 3, thermometric thermal resistance 4 and stirrer 5 by data communication converter 6 with control computer 7 and be connected; Specifically calibration cell 2, with the UV of ATR detection probe ?vis spectrometer 3, thermometric thermal resistance 4 be connected with data communication converter 6 by data line with stirrer 5.Data communication converter 6 is connected by data line with control computer 7.Calibration cell 2, with the UV of ATR detection probe ?the data of vis spectrometer 3, thermometric thermal resistance 4 and stirrer 5 export by data communication converter 6(AD/DA) be uploaded to and control computer 7 and process.Calibration cell 2 is for solution temperature in crystallization control still, stirrer 5 is guaranteed solution concentration homogeneity in crystallization kettle, with the UV of ATR detection probe ?vis fiber spectrometer 3 obtain solution A TR ?UV spectrum, thermometric thermal resistance 4 is measured solution temperature in still, data communication converter (AD/DA) 6 changes and is uploaded to control computer 7 for the AD/DA of communication data, control computer 7 by the spectrum of Real-time Obtaining and temperature information substitution concentration detection model, calculate solution concentration online demonstration and real time access.The concentration specific embodiment of the online concentration detection apparatus testing drug active component shown in application drawing 1 is as embodiment 1 ?3 below.
Embodiment 1
The online concentration of paracetamol crystallisation by cooling process detects, and solvent is ethanol.
(1) concentration calibration: in crystallization kettle, prepare 5 groups of concentration and be 0.18,0.22,0.28,0.32,0.36(g/g solvent) paracetamol solution, the paracetamol ethanolic solution of testing above-mentioned variable concentrations is paracetamol saturation solubility in alcohol solvent corresponding 20 DEG C, 30 DEG C, 40 DEG C, 45 DEG C, 50 DEG C time respectively.Taking concentration group 0.36(g/g solvent) solution is example explanation test process: in crystallization kettle 1, adds 36g paracetamol and 100g absolute ethyl alcohol, under 60 DEG C of conditions, stirs 1h wiring solution-forming.By the UV with ATR detection probe ?4 tests of vis fiber spectrometer 3 and thermometric thermal resistance obtain solution A TR ?UV spectrum and the interior solution temperature of crystallization kettle 1; Specifically control computer 7 programmed control calibration cells 2 and regulate and control solution temperature, respectively solution temperature be under 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C, 60 DEG C (thermometric thermal resistance 4 records) conditions, store corresponding A TR ?UV spectrum, add that to measure next group concentration after ethanol dilution be 0.32(g/g solvent) solution spectrum data, by that analogy.Institute's obtain solution and every group of solution phase should get ATR ?UV spectroscopic temperature point as shown in table 1 below, be wherein with * mark as checksum set, remainder data is as training set.
Table 1 paracetamol concentration calibration experimental matrix
(2) foundation of detection model: choose absorbance corresponding to 6 place's wavelength in absorption peak in this example and carry out data regression, selected wavelength is 254.08nm, 255.57nm, 256.42nm, 257.27nm, 257.7nm, 258.76nm.Taking solution concentration y as dependent variable, in training set, spectrum and temperature data are independent variable, adopt partial least square method to return and draw the preliminary parameter of concentration detection model, and then draw concentration detection model taking checksum set concentration detection residual mean square (RMS) root minimum as judgment basis
middle optimization correlation coefficient a=0.07365, b=0.001693, c
1to c
6in table 2.
The table 2 paracetamol concentration detection model correlation coefficient of being correlated with
| R | R 1(254.08nm) | R 2(255.57nm) | R 3(256.42nm) | R 4(257.27nm) | R 5(257.7nm) | R 6(258.76nm) |
| c | ‐0.8093 | ‐1.4955 | ‐3.9416 | 3.7023 | 3.3352 | ‐0.5860 |
(3) concentration is calculated automatically: weigh 70g paracetamol and be placed in crystallization kettle, add 250ml ethanol, stir 200rpm, maintain 1h under 60 DEG C of conditions of chuck circulating temperature and guarantee that solute dissolves completely, be cooled to 50 DEG C and add crystal seed, after balance 10min, carry out crystallisation by cooling, maintain 0.2 DEG C/min rate of temperature fall.Open online concentration detection system described in the utility model, control computer expert and cross data communication (AD/DA) converter by the above-mentioned 6 absorbance R of wavelength place of ATR detection probe Real-time Obtaining and the solution temperature T of thermometric thermal resistance Real-time Obtaining, and the concentration detection model of setting up in substitution step (2), automatically calculate y value and obtain real-time solution concentration.The temperature of above-mentioned experimentation and concentration are in the variation range of step (1).
(4) the online detection display of concentration information and record: controlling in the man-machine interaction interface that obtains of computer programming, interfaces windows shows current crystallization process solution concentration in real time, simultaneously in backstage real time record in txt document.
In crystallization process, with pipe front end be equipped with aperture 1 ?the syringe sampling of 10 μ m micro-strainers, sample altogether 8 times, adopt gravimetric method analytical solution concentration, online detection with gravimetric method result comparative result seen Fig. 2.As seen from Figure 2, within the 200min crystallisation by cooling time period, solution concentration is down to 0.15g/g solvent from 0.36g/g solvent, and the measured value of online testing result and gravimetric method compares, and effectively mean square deviation is 0.28%.
Embodiment 2
Methyl hydroxybenzoate crystallisation by cooling solution concentration detects online, and solvent is water/ethanol (50%v/v).
(1) concentration calibration: in crystallization kettle, prepare 5 groups of concentration and be 0.13,0.22,0.37,0.50,0.66(g/g solvent) Metagin ester solution, methyl hydroxybenzoate saturation solubility in water/ethanol (50%v/v) solvent while distinguishing corresponding 20,30,40,45,50 DEG C, taking concentration group 0.66(g/g solvent) solution is example explanation gatherer process: in crystallization kettle, adds 66g methyl hydroxybenzoate and 100g water/ethanol (50%v/v), under 60 DEG C of conditions, stirs 1h wiring solution-forming.By the UV with ATR detection probe ?4 tests of vis fiber spectrometer 3 and thermometric thermal resistance obtain solution A TR ?UV spectrum and the interior solution temperature of crystallization kettle 1; Specifically control computer 7 programmed control calibration cells 2 and regulate and control solution temperature, under 40,45,50,55,60 DEG C of (thermometric thermal resistance records) conditions of solution temperature, store respectively ATR ?UV spectrum, add water/ethanol (50%v/v) to dilute and measure next group concentration be 0.50(g/g solvent) solution spectrum data, by that analogy.It is as shown in table 3 below that institute's obtain solution and every group of solution phase should be got spectroscopic temperature point, is wherein with * mark as checksum set, and remainder data is as training set.
Table 3 methyl hydroxybenzoate concentration calibration experimental matrix
(2) foundation of detection model: choose the corresponding absorbance of 6 place's wavelength in absorption peak in this example and carry out data regression, selected wavelength is that 259.4nm, 263.44nm, 265.57nm, 267.48nm, 269.18nm, 272.57nm. are taking solution concentration y as dependent variable, in training set, spectrum and temperature data are that independent variable adopts partial least square method recurrence to draw the preliminary parameter of concentration detection model, and then draw concentration detection model taking checksum set concentration detection residual mean square (RMS) root minimum as judgment basis
middle optimization correlation coefficient a=?0.05409, b=0.001257, c
1to c
6see the following form 4.
The table 4 Metagin ester concentration detection model correlation coefficient of being correlated with
| R | R 1(259.4nm) | R 2(263.44nm) | R 3(265.57nm) | R 4(267.48nm) | R 5(269.18nm) | R 6(272.57nm) |
| c | 3.006 | ‐0.3779 | ‐2.16 | ‐2.046 | ‐0.6573 | 2.9278 |
(3) concentration is calculated automatically: weigh 120g methyl hydroxybenzoate in crystallization kettle, add 250ml water/ethanol (50%v/v), stir 200rpm, maintain 1h under 60 DEG C of conditions of chuck circulating temperature and guarantee that solute dissolves completely, be cooled to 50 DEG C and add crystal seed, after balance 10min, carry out crystallisation by cooling, maintain 0.2 DEG C/min rate of temperature fall.Open online concentration detection system described in the utility model, control computer expert and cross data communication (AD/DA) converter by the above-mentioned 6 absorbance R of wavelength place of ATR detection probe Real-time Obtaining and the solution temperature T of thermometric thermal resistance Real-time Obtaining, and the concentration detection model of setting up in substitution step (2), automatically calculate y value and obtain real-time solution concentration.The temperature of above-mentioned experimentation and concentration are in the variation range of step (1).
(4) the online detection display of concentration information and record: controlling in the man-machine interaction interface that obtains of computer programming, interfaces windows shows current crystallization process solution concentration in real time, simultaneously in backstage real time record in txt document.
In crystallization process, with pipe front end be equipped with aperture 1 ?the syringe sampling of 10 μ m micro-strainers, adopt gravimetric method analytical solution concentration, online testing result compares with the measured value of gravimetric method, effective mean square deviation is 0.59%.
Embodiment 3
Exalgine crystallisation by cooling solution concentration is detected online, and ethanol is solvent.
(1) concentration calibration: in crystallization kettle, prepare 5 groups of concentration and be 0.21,0.28,0.38,0.42,0.46(g/g solvent) to methyl acetanilide amine aqueous solution, respectively corresponding 25,30,40,45,50 DEG C time to exalgine saturation solubility in alcohol solvent, taking concentration group 0.46(g/g solvent) solution is example explanation gatherer process: in crystallization kettle, adds 46g to exalgine and 100g ethanol, under 60 DEG C of conditions, stirs 1h wiring solution-forming.By the UV with ATR detection probe ?4 tests of vis fiber spectrometer 3 and thermometric thermal resistance obtain solution A TR ?UV spectrum and the interior solution temperature of crystallization kettle 1; Specifically control computer 7 programmed control calibration cells 2 and regulate and control solution temperature, under 40,45,50,55,60 DEG C of (thermometric thermal resistance 4 records) conditions of solution temperature, store respectively ATR ?UV spectrum, adding ethanol to dilute and measuring next group concentration is 0.42(g/g solvent) solution spectrum data, by that analogy.It is as shown in table 5 below that institute's obtain solution and every group of solution phase should be got spectroscopic temperature point, is wherein with * mark as checksum set, and remainder data is as training set.
Table 5 is to exalgine concentration calibration experimental matrix
(2) foundation of detection model: choose the corresponding absorbance of 5 place's wavelength in absorption peak in this example and carry out data regression, selected wavelength is that 255.78nm, 256.85nm, 257.49nm, 258.55nm, 259.40nm. are taking solution concentration y as dependent variable, in training set, spectrum and temperature data are that independent variable adopts partial least square method recurrence to draw the preliminary parameter of concentration detection model, and then draw concentration detection model taking checksum set concentration detection residual mean square (RMS) root minimum as judgment basis
middle optimization correlation coefficient a=0.0519, b=0.001156, c
1to c
5see the following form 6.
Table 6 is to the relevant correlation coefficient of exalgine concentration detection model
| R | R 1(255.78nm) | R 2(256.85nm) | R 3(257.49nm) | R 4(258.55nm) | R 5(259.40nm) |
| c | 2.0016 | ‐0.2759 | 2.1436 | ‐2.1066 | ‐0.6573 |
(3) concentration is calculated automatically: weigh 90g exalgine is placed in to crystallization kettle, add 250ml ethanol, stir 200rpm, maintain 1h under 60 DEG C of conditions of chuck circulating temperature and guarantee that solute dissolves completely, be cooled to 50 DEG C and add crystal seed, after balance 10min, carry out crystallisation by cooling, maintain 0.2 DEG C/min rate of temperature fall.Open online concentration detection system described in the utility model, control computer expert and cross data communication (AD/DA) converter by the above-mentioned 6 absorbance R of wavelength place of ATR detection probe Real-time Obtaining and the solution temperature T of thermometric thermal resistance Real-time Obtaining, and the concentration detection model of setting up in substitution step (2), automatically calculate y value and obtain real-time solution concentration.The temperature of above-mentioned experimentation and concentration are in the variation range of step (1).
(4) the online detection display of concentration information and record: controlling in the man-machine interaction interface that obtains of computer programming, interfaces windows shows current crystallization process solution concentration in real time, simultaneously in backstage real time record in txt document.
In crystallization process, with pipe front end be equipped with aperture 1 ?the syringe sampling of 10 μ m micro-strainers, adopt gravimetric method analytical solution concentration, online testing result compares with the measured value of gravimetric method, effective mean square deviation is 1.12%.
Claims (3)
- Based on ATR ?the online concentration detection apparatus of crystallisation by cooling process medicine activity component of UV, it is characterized in that: comprise crystallization kettle, calibration cell, with the UV of ATR detection probe ?vis fiber spectrometer, thermometric thermal resistance, stirrer, data communication converter and control computer; With the UV of ATR detection probe ?vis spectrometer, thermometric thermal resistance and stirrer be directly installed in crystallization kettle; Crystallization kettle is connected with calibration cell; Calibration cell, with the UV of ATR detection probe ?vis spectrometer, thermometric thermal resistance and stirrer by data communication converter with control computer and be connected.
- 2. the online concentration detection apparatus of crystallisation by cooling process medicine activity component according to claim 1, is characterized in that: described calibration cell, with the UV of ATR detection probe ?vis spectrometer, thermometric thermal resistance be connected with data communication converter by data line with stirrer.
- 3. the online concentration detection apparatus of crystallisation by cooling process medicine activity component according to claim 1, is characterized in that: described data communication converter is crossed data line with control computer expert and is connected.
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| CN201420018040.4U CN203870015U (en) | 2014-01-10 | 2014-01-10 | On-line concentration detection device for active pharmaceutical ingredient in cooling crystallization process |
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| CN201420018040.4U CN203870015U (en) | 2014-01-10 | 2014-01-10 | On-line concentration detection device for active pharmaceutical ingredient in cooling crystallization process |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103760124A (en) * | 2014-01-10 | 2014-04-30 | 华南理工大学 | Online concentration detection device and method of active pharmaceutical ingredients in cooling crystallization process |
| CN109030303A (en) * | 2018-07-24 | 2018-12-18 | 中国石油大学(北京) | The electrical impedance spectrometry on-line measurement device of crystal grain size in crystallization process |
| CN112362605A (en) * | 2020-10-27 | 2021-02-12 | 华南理工大学 | Method for monitoring continuous crystallization process of benzotriazole by online ultraviolet |
-
2014
- 2014-01-10 CN CN201420018040.4U patent/CN203870015U/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103760124A (en) * | 2014-01-10 | 2014-04-30 | 华南理工大学 | Online concentration detection device and method of active pharmaceutical ingredients in cooling crystallization process |
| CN103760124B (en) * | 2014-01-10 | 2016-08-17 | 华南理工大学 | The online concentration detection method of crystallisation by cooling Procedures Drug active component |
| CN109030303A (en) * | 2018-07-24 | 2018-12-18 | 中国石油大学(北京) | The electrical impedance spectrometry on-line measurement device of crystal grain size in crystallization process |
| CN112362605A (en) * | 2020-10-27 | 2021-02-12 | 华南理工大学 | Method for monitoring continuous crystallization process of benzotriazole by online ultraviolet |
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