WO2000040950A1 - Reaction monitoring - Google Patents
Reaction monitoring Download PDFInfo
- Publication number
- WO2000040950A1 WO2000040950A1 PCT/SE1999/002473 SE9902473W WO0040950A1 WO 2000040950 A1 WO2000040950 A1 WO 2000040950A1 SE 9902473 W SE9902473 W SE 9902473W WO 0040950 A1 WO0040950 A1 WO 0040950A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- reaction
- determining
- extent
- chemical reaction
- anyone
- Prior art date
Links
Classifications
-
- 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
- G01N21/65—Raman scattering
-
- 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
- G01N21/65—Raman scattering
- G01N2021/651—Cuvettes therefore
-
- 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
- G01N21/65—Raman scattering
- G01N2021/653—Coherent methods [CARS]
- G01N2021/656—Raman microprobe
Definitions
- the present invention relates to a method for monitoring a chemical reaction of pharmaceutical relevance.
- the manufacture of a pharmaceutical substance often involves a reaction process step, such as a synthesis, wherein original constituents react with each other after being mixed in a reaction vessel. During the reaction process, while the desired substance is formed, the original reactants are consumed.
- the reaction process step of the manufacturing process is a batch process and it is economically desirable to process a batch as fast as possible. Further, undesired by-products can develop in the reaction vessel if the manufactured substance is left in the reaction vessel after the reaction is completed. Therefore, it is desired to know when the reaction is completed.
- a conventional method for determining when the reaction is completed is to measure the concentration of the substance produced. This is often combined with a measurement of the concentration of one or more of the original constituents. By experience it is known within what ranges the concentrations should arrive.
- spectroscopy such as NIR (Near Infra-Red), MIR (Mid Infra-Red) and ATR (Attenuated Total Reflectance) in combination, or Raman spectroscopy.
- the resulting spectral information is related to said concentrations.
- the result is determined by measuring peak height and/or peak area for one or more peaks at significant wavelengths, and comparing the measurements to relevant references.
- the above described prior art methods of determining the point of completion of the reaction involves a time delay which is added to the mean time required for completing a specific reaction.This is done in order to ascertain that the reaction is mostly completed when the measurement is performed.. Thereby the variance of the reaction time period is taken into account. The addition of the time delay is performed in order to avoid making excessive measurements.
- spectroscopic methods have been developed to enable continuous monitoring of the reaction process.
- Known methods include Raman spectroscopy wherein a single wavelength is irradiated towards the solution, which scatters a spectrum, called Raman spectrum.
- Raman is advantageous due to the relatively narrow peaks of the resulting Raman spectrum, which makes it easier to distinguish an individual peak related to a specific substance of the solution.
- the apparatus for performing such Raman monitoring is sufficiently fast in order to produce relevant spectra serving the purpose of the monitoring.
- the evaluation of the spectra in order to determine the concentration of a substance still relies on a determination of the peak heights or areas. This in turn requires a relevant calibration of the spectra and a comparison of the calibrated spectra with a relevant reference spectrum. To enhance the calibration, multivariate methods, such as partial least squares regression, may be employed.
- One object of this invention is to provide a method for monitoring a reaction, which method provides for an accurate determination of the extent of the reaction.
- the objects are achieved by a method for monitoring a chemical reaction of pharmaceutical relevance, in accordance with the present invention.
- the method comprises the steps of:
- MVDA multivariate data analysis
- the present invention provides for continuous monitoring of the reaction and obtaining of consecutive Raman spectra, it is possible, by applying the MVDA, to easily follow the progress of the reaction.
- the changes of the conditions within the reaction vessel are efficiently detected by the MVDA and mirrored thereby in a single or a few main components.
- the main component(s) is then processed in order to determine how the changes proceed with time.
- the MVDA generates a result that is relative to constituents and physical properties internal to the reaction, and, consequently, no particular reference is needed.
- An embodiment of the present invention is characteristic for the invention in that no calibration using reference measurements of objects having a known composition is needed. Principally, the only response variable used, if any, is the reaction time, or an amount proportional to the reaction time.
- Fig. 1 illustrates schematically an arrangement for monitoring a reaction, such as a synthesis
- Fig. 2 illustrates Raman spectra obtained at different points of a first reaction
- Fig. 3 is a scores plot related to Fig. 2;
- Fig. 4 is a loadings plot related to Fig. 2;
- Fig. 5 illustrates Raman spectra of different compounds related to a second reaction
- Fig. 6 illustrates Raman spectra obtained at different points of the second reaction
- Fig. 7 is a scores plot related to Fig. 6;
- Fig. 8 is a scores plot related to Fig. 6;
- Fig. 9 shows diagrams of a spectrum difference and loadings respectively.
- Fig. 1 an example of an arrangement for reaction monitoring is shown.
- the arrangement comprises a Raman spectrometer equipped with a charge coupled device (CCD) detector 1 , a holographic transmission grating 3, a laser 5, an optical fibre 7, and an optical interface 9; and an evaluation device 11.
- CCD charge coupled device
- Reference character 13 denotes a reaction vessel, the contents of which is monitored.
- the vessel 13 has a wall of glass through which the monitoring may be performed.
- the reaction vessel contains a solution comprising different constituents, such as reactants, catalysts etc., which are required for producing a desired substance of pharmaceutical relevance, below simply referred to as the substance.
- the solution is generally stirred, subjected to a particular temperature, etc., in order to provide appropriate conditions for the reaction to take place.
- the optical interface 9 is appropriately positioned either at a distance, determined by the focus, from the outer surface of the glass wall of the vessel 13 or within the vessel 13 lowered into the solution.
- Monochromatic radiation is irradiated by the laser 5 and led through the optical fibre 7 to the optical interface 9 coupling the radiation into the solution.
- the solution scatters a spectrum, which is caught by the optical interface and led by the optical fibre to the CCD detector.
- the optical fibre may be appropriately constituted in any appropriate way as will be known to one skilled in the art.
- said optical fibre could be constituted by a bundle of two or several fibres, one or more used for guiding the monochromatic radiation to the vessel and one or more other fibres used for guiding the scattered radiation back through the holographic transmission grating 3 to the CCD.
- the Raman spectrum thus sampled by means of the CCD detector is then processed by the evaluation device, which may be a general purpose computer executing a proper set of instructions for performing the processing or a special purpose computer specifically structured and/or programmed
- the processing of the CCD detector output which in the following is referred to as the spectrum sample, aims at monitoring the reaction in order to accurately determine the extent of the reaction.
- the determination of the extent of the reaction may be a determination of how far the reaction has proceeded or, ultimately, of the point of time when the reaction is finished.
- the processing comprises the main steps of:
- step c) comprises several alternative determinations which may be optionally combined.
- step a) is simply performed by reading the output of the CCD detector.
- the output consists of a number of values, here labelled spectrum values, at different wavelengths.
- an MVDA multivariate data analysis
- the prior art methods of monitoring a chemical reaction are based on the determination of peak height or area changes of one or more peaks related to a specific substance of the solution.
- the reaction may be determined to be finished when the peak height/area is no longer changing or when it has reached a predetermined value.
- Such measurements are dependent on momentary conditions, such as laser intensity, changing from one sample to the other.
- the prior art methods require the spectrum sample to be calibrated against an explicitly known internal or external reference spectrum sample, in order to ascertain the peak values of specific peaks of the Raman spectrum.
- the calibration is made with a different independent analytical result for a similar sample.
- the described requirements make the prior art methods complex.
- multivariate data analysis has been inventively used as a means for eliminating the need for such references.
- PCA principal component analysis
- PLS partial least squares
- the spectrum samples are placed as rows in matrix X, having n rows and k columns. Thus, each row represents a spectrum sample and each column represents a single wavelength.
- the matrix X is approximated in terms of the product of two smaller matrices T and P'. These matrices capture the essential patterns of X. E is a noise matrix. If, for example, X is a 20x10 matrix, i.e. 20 spectrum samples and 10 wavelengths, then T is a 20xA matrix and P' is a Ax 10 matrix. A represents the number of principal components resulting from the PCA.
- the Principal Component model is a plane that is spanned by the A rows of the matrix P'.
- Each principal component consists of two vectors, the score vector t and the loading vector p.
- the score vector t contains a score value for each spectrum sample, and this score value tells how the spectrum sample is related to the other spectrum samples in that particular principal component.
- the loading vector tells which spectral features in the original spectrum samples that are captured by the principal component studied.
- an appropriate number A of principal components is determined by means of e.g. cross validation. In this embodiment one or a few principal components are determined. As will be apparent below, the first principal components capture the largest variation in the matrix X, which va ⁇ ation is closely related to the reaction process Consequently, the first few p ⁇ ncipal components are usable for the desirable momto ⁇ ng purposes of this invention
- PLS has been used as an alternative to the PCA PLS is a projection and regression method involving the X mat ⁇ x and a y vector (or mat ⁇ x)
- the time that has lapsed from the start of the reaction is inventively used as y m connection with Raman spectroscopy
- the PLS method works in a similar manner as PCA A difference is that while PCA captures as much of the va ⁇ ation of X as possible in each component, PLS calculates components that both capture the va ⁇ ation of X and correlates to the va ⁇ ation m y
- the PLS method is to be further discussed with reference to the below equations 2-5
- the loading weight vector w ⁇ where a denotes PLS component number a, shows the spectral features in X that correlate with y, calculated as in equation 2
- the score vector t a which can be interpreted m the same way as in PCA, is calculated as in equation 3
- a scalar coefficient c a is then calculated (eqn 4) which in turn together with t ⁇ constitutes an equation for y, where f is a residual with non-modelled va ⁇ ation m y (eqn 5)
- the number of PLS components to be used is often selected with cross validation and/or independent test sample sets As m the PCA case, we are here mamly interested m the first few PLS components
- SNV Standard Normal Variate
- Equation 6 shall be repeated for all k wavenumbers in the spectrum.
- SNV multiplicative signal correction
- the main components thus generated are related to latent variables of the spectrum samples, which latent variables are indicative of the progress of the reaction.
- step c) one or more of several different determinations are performed, basically by means of the first main component of the PCA or the PLS.
- an indication value inherent in said first main component is determined.
- This indication value is indicative of the extent of the reaction and may for example represent the concentration of a compound.
- What is actually used as the indication value is a score value of the score vector of the first main component.
- the corresponding loading vector is evaluated in parallel.
- the indication value or, generally, a vector of indication values, i.e. the score vector, is then used in further one or more different ways, dependent on what evaluation is requested.
- One way to proceed is to determine if the progress of the reaction follows a typical schedule by monitoring the pathway of the score trace generated by consecutive MVDAs. This score trace is compared with a predetermined pathway, for example, determined as a mean of several pathways generated during previously run reactions. If the present pathway deviates excessively from the predetermined pathway, then it is determined that reaction is not proceeding typically By means of this determination it is possible to stop erroneous reactions at an early stage, thereby saving time of manufacture
- Another way to proceed is to compare the present score vector with a predetermined set of score vectors covenng the whole reaction process from the beginning to the end
- the reaction extent represented by the predetermined score vector causing the smallest difference to the present score vector is taken as the extent which the present reaction has reached
- the score vector to determine when the reaction is finished This is done by determining a rate of change of consecutive indication values, l e score values
- the rate of change is related to the extent of the reaction in that the rate is zero when an equi b ⁇ um is reached, which of course is the case when the reaction is finished.
- a stop limit could be defined When the rate of change decreases below said stop limit it is determined that the reaction is finished.
- the score values could be used as indication values for determining the rate of change. In this way it is instantly and accurately determined that the reaction is finished, thereby saving time of manufacture
- Fig 2 four different diagrams of the Raman intensity versus wavenumber are shown for the hydrolysis at four different points of time du ⁇ ng the reaction process. Arrows show the development of the Raman intensity, or peak height, at four different wavenumbers It can be seen that the height of three of the peaks decreases with time while the height of one of the peaks increases with time Decreasing peak heights represent the ethyl acetate and increasing peak heights represent both ethanol and acetic acid, since their peaks overlap each other
- Fig. 3 the scores of the first mam component, l e p ⁇ ncipal component, (PCI) are plotted for PCAs performed on Raman spectra obtained from the hydrolysis at different points It is evident from the plot how the reaction proceeds Fig 4 shows a corresponding loading plot determined on the complete X matrix.
- the loading plot illustrates spectral features responsible for the pattern of the score plot.
- the score plot is usable for determining the extent of the reaction as described above. For example, it is evident from the plot that at the end of the reaction the rate of change approaches zero.
- Metoprolol is the result of a reaction between Meepb, short for l-(2,3-epoxypropoxy)-4-(2-methoxyethyl)benzene (or p- methoxyethyl-epoxypropoxybenzene), and Isopropylamine.
- the reaction takes place in an Isopropanol solvent.
- the reaction scheme is: C 12 H 16 O 3 + C 3 H 9 N -> C 15 H 25 NO 3 .
- Fig. 5 the Raman spectra for the four compounds of the solution, during the ongoing reaction all present at the same time, are shown. It is to be noted that particularly the spectra of the Meepb and the Metoprolol base are very similar, and that the spectra of the other compounds substantially overlap with the Metoprolol base spectrum. This makes it extremely difficult to use the prior art methods for monitoring the reaction. As is illustrated in Fig. 6, the overlapping peaks result in a Raman spectrum having few and weak peaks changing during the progress of the reaction.
- MVDA and more particularly PCA
- Fig. 8 shows a score plot of a PLS-analysis, to be compared to the PCA score plot in Fig. 7.
- the upper diagram of Fig. 9 illustrates the difference between a first spectrum sampled at the beginning of the reaction and a second spectrum sampled at the end of the reaction.
- the lower diagram of Fig. 9 illustrates a plot of the loadings of the first main component (PCI). The plot is based on the full X matrix. Note the similarity, which confirms that the loadings of the first component represent the spectral changes taking place during the reaction process.
- PCI main component
- the method of the present invention involves feedback control of the reaction.
- the feedback control is dependent on the results obtained by the MVDA.
- the PCA or PLS components are further evaluated in order to obtain knowledge of whether the chemical reaction proceeds as required or some parameter should be changed in order for it to proceed as required.
- the feedback control can be based on changes in scores and loadings which are in response to a change in temperature.
- the determination of whether the temperature has changed is based on,, for example, the derivative of the scores plot for the first few PCA or PLS components. The thermostat environment surrounding the reaction vessel is then adjusted accordingly.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU21371/00A AU758733B2 (en) | 1999-01-05 | 1999-12-22 | Reaction monitoring |
JP2000592619A JP2002534674A (en) | 1999-01-05 | 1999-12-22 | Reaction monitoring |
EP99965685A EP1147401A1 (en) | 1999-01-05 | 1999-12-22 | Reaction monitoring |
NZ512434A NZ512434A (en) | 1999-01-05 | 1999-12-22 | Reaction monitoring |
CA002354459A CA2354459A1 (en) | 1999-01-05 | 1999-12-22 | Reaction monitoring |
KR1020017008496A KR20010101371A (en) | 1999-01-05 | 1999-12-22 | Reaction monitoring |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9900030A SE9900030D0 (en) | 1999-01-05 | 1999-01-05 | Reaction monitoring |
SE9900030-9 | 1999-01-05 |
Publications (1)
Publication Number | Publication Date |
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WO2000040950A1 true WO2000040950A1 (en) | 2000-07-13 |
Family
ID=20414039
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1999/002473 WO2000040950A1 (en) | 1999-01-05 | 1999-12-22 | Reaction monitoring |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1147401A1 (en) |
JP (1) | JP2002534674A (en) |
KR (1) | KR20010101371A (en) |
CN (1) | CN1332844A (en) |
AU (1) | AU758733B2 (en) |
CA (1) | CA2354459A1 (en) |
NZ (1) | NZ512434A (en) |
SE (1) | SE9900030D0 (en) |
WO (1) | WO2000040950A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103196864A (en) * | 2013-04-12 | 2013-07-10 | 西北大学 | Method of researching reaction mechanism by utilizing MCR-ALS (Multivariate Curve Resolution-Alternating Least Squares) combined with infrared online spectrum |
EP2895846A4 (en) * | 2012-09-14 | 2016-06-08 | Halliburton Energy Services Inc | Systems and methods for monitoring chemical processes |
Families Citing this family (5)
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US7141769B2 (en) * | 2005-04-01 | 2006-11-28 | Cem Corporation | Spectroscopy-based real-time control for microwave-assisted chemistry |
MX2013003038A (en) * | 2010-09-17 | 2013-05-01 | Abbvie Inc | Raman spectroscopy for bioprocess operations. |
JP6620100B2 (en) * | 2013-12-27 | 2019-12-11 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Methods and systems for preparing synthetic multicomponent biotechnological and chemical process samples |
CN105548141A (en) * | 2016-01-22 | 2016-05-04 | 中国科学院城市环境研究所 | Method for online monitoring of pollutants in water |
CN106568728A (en) * | 2016-06-30 | 2017-04-19 | 华南理工大学 | Method for rapidly and accurately judging pulp xanthation reaction endpoint |
Citations (6)
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WO1996010009A1 (en) * | 1994-09-28 | 1996-04-04 | Exxon Chemical Patents Inc. | A method for controlling polyol ester conversion using near or mid-infrared analysis |
EP0751388A2 (en) * | 1995-06-28 | 1997-01-02 | Kyoto Dai-ichi Kagaku Co., Ltd. | Method of optically measuring a component in solution |
US5596196A (en) * | 1995-05-24 | 1997-01-21 | Ashland Inc. | Oxygenate analysis and control by Raman spectroscopy |
US5610836A (en) * | 1996-01-31 | 1997-03-11 | Eastman Chemical Company | Process to use multivariate signal responses to analyze a sample |
US5638172A (en) * | 1994-05-27 | 1997-06-10 | Eastman Chemical Company | On-line quantitative analysis of chemical compositions by raman spectrometry |
DE19810917A1 (en) * | 1998-03-13 | 1999-09-16 | Buehler Ag | Calibration method used in evaluation of measured spectra |
-
1999
- 1999-01-05 SE SE9900030A patent/SE9900030D0/en unknown
- 1999-12-22 WO PCT/SE1999/002473 patent/WO2000040950A1/en not_active Application Discontinuation
- 1999-12-22 AU AU21371/00A patent/AU758733B2/en not_active Ceased
- 1999-12-22 KR KR1020017008496A patent/KR20010101371A/en not_active Application Discontinuation
- 1999-12-22 CA CA002354459A patent/CA2354459A1/en not_active Abandoned
- 1999-12-22 JP JP2000592619A patent/JP2002534674A/en active Pending
- 1999-12-22 NZ NZ512434A patent/NZ512434A/en unknown
- 1999-12-22 EP EP99965685A patent/EP1147401A1/en not_active Withdrawn
- 1999-12-22 CN CN99815392A patent/CN1332844A/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5638172A (en) * | 1994-05-27 | 1997-06-10 | Eastman Chemical Company | On-line quantitative analysis of chemical compositions by raman spectrometry |
WO1996010009A1 (en) * | 1994-09-28 | 1996-04-04 | Exxon Chemical Patents Inc. | A method for controlling polyol ester conversion using near or mid-infrared analysis |
US5596196A (en) * | 1995-05-24 | 1997-01-21 | Ashland Inc. | Oxygenate analysis and control by Raman spectroscopy |
EP0751388A2 (en) * | 1995-06-28 | 1997-01-02 | Kyoto Dai-ichi Kagaku Co., Ltd. | Method of optically measuring a component in solution |
US5610836A (en) * | 1996-01-31 | 1997-03-11 | Eastman Chemical Company | Process to use multivariate signal responses to analyze a sample |
DE19810917A1 (en) * | 1998-03-13 | 1999-09-16 | Buehler Ag | Calibration method used in evaluation of measured spectra |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2895846A4 (en) * | 2012-09-14 | 2016-06-08 | Halliburton Energy Services Inc | Systems and methods for monitoring chemical processes |
CN103196864A (en) * | 2013-04-12 | 2013-07-10 | 西北大学 | Method of researching reaction mechanism by utilizing MCR-ALS (Multivariate Curve Resolution-Alternating Least Squares) combined with infrared online spectrum |
Also Published As
Publication number | Publication date |
---|---|
AU758733B2 (en) | 2003-03-27 |
SE9900030D0 (en) | 1999-01-05 |
KR20010101371A (en) | 2001-11-14 |
CN1332844A (en) | 2002-01-23 |
AU2137100A (en) | 2000-07-24 |
JP2002534674A (en) | 2002-10-15 |
EP1147401A1 (en) | 2001-10-24 |
NZ512434A (en) | 2003-12-19 |
CA2354459A1 (en) | 2000-07-13 |
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