Analytical equipment, analytical method, and program

Abstract

The present invention provides an analytical device for estimating the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown, comprising: a spectrum acquisition unit that acquires spectral spectra of the chemical reaction system at multiple time points; a calculation unit that calculates characteristic quantities of the spectral spectra at each time point from the spectral spectra at multiple time points; and an estimation unit that estimates the endpoint of the chemical reaction based on the changes in the characteristic quantities calculated by the calculation unit. Furthermore, the present invention provides an analytical method using the analytical device and a program that makes a computer function as the analytical device.

Description

[Technical Field]

[0001] This invention relates to an analytical device, an analytical method, and a program. [Background technology]

[0002] Patent Document 1 describes a method for controlling the operation of a plant based on measurements obtained by near-infrared analysis of a sample, characterized in that the sample is subjected to near-infrared analysis based on a calibration curve prepared in advance, the measurements obtained by the near-infrared analysis method are compared with an acceptable value, if the measurements obtained are outside the acceptable value, analysis is performed by a general analysis method, the measurements obtained by the general analysis method are compared with an acceptable value, if the measurements obtained by the general analysis method are within the acceptable value, past near-infrared analysis data is input to obtain a predicted value, if the predicted value is outside the acceptable value, the near-infrared analyzer is inspected, and if the predicted value is within the acceptable value, the calibration curve is supplemented and evaluated (Claim 1). Patent Document 2 describes the following: "When the titer of an atomic group is f, the response from the analyzer is r, the number of unstable intermediates is L, its quantitative function is F(r), the number of known components is M, the number of reaction solution samples to be analyzed is n, the concentration of the known components is c, the sum of the concentrations * titers of the components in the sample is C, and the number of analyses is m, the parameters of the unknown quantitative function F(r) are determined by numerical calculation to minimize the value represented by Equation 1, and quantification is performed using this quantitative function." (Abstract) Patent Document 3 describes a method for monitoring pharmaceutical-related chemical reactions, comprising: continuously obtaining Raman spectral samples of a solution of chemical components contained in a reaction vessel by substantially monochromatic emission of the solution; detecting scattered emission; processing the Raman spectral samples by means of multivariate data analysis (MVDA) for a first principal component related to a potential variability index of the progress of the reaction, wherein the multivariate data analysis is independent of calibration using reference measurements of an object having a known composition; and measuring the progress of a chemical reaction based on at least one first principal component, and optionally based on one or more principal components produced from one or more previously performed reactions of the same type. (Claim 1) Patent Document 4 describes an optical analysis system comprising: "a chemical reaction system for synthesizing a first raw material and a second raw material to obtain a product, comprising: an irradiation unit that irradiates the first raw material and the second raw material with irradiation light before the start of synthesis, and irradiates the mixture containing the first raw material, the second raw material, and the product after the start of synthesis with irradiation light; a detection unit that detects the measurement light based on the irradiation light irradiated by the irradiation unit, which contains information regarding the spectral spectra of the first raw material, the second raw material, and the mixture; and a calculation unit that calculates the spectral spectra of the first raw material, the second raw material, and the mixture, and calculates the spectral spectrum of the product based on each spectral spectrum, wherein the product includes either an unisomerized compound or a pair of compounds that are optical isomers of each other." (Claim 1). Patent Document 5 describes a method for spectrally analyzing a plurality of measurement spectra using a multivariate curve decomposition (MCR) method, which is based on the premise that the measurement spectrum obtained by measuring a sample is represented by a linear combination of the product of a predetermined number of pure spectra of a predetermined number of components and the concentration value of each pure spectrum, wherein the method involves separating the pure spectra of the predetermined number of components from a plurality of measurement spectra and calculating the concentration value of each pure spectrum, setting an equilibrium model according to the equilibrium state of the sample in which three or more chemical species coexist, setting at least one chemical equilibrium equation according to the equilibrium model, and starting the MCR for the plurality of measurement spectra. (A) Fit the concentration curve based on the chemical equilibrium equation to the calculated concentration value to obtain the optimal value of the thermodynamic parameter constituting the chemical equilibrium equation. A spectral analysis method is described in claim 1, characterized by repeating the processes of (A) and (B), which include (B) obtaining a new concentration value from the chemical equilibrium equation using the optimal value of the thermodynamic parameter, and using the new concentration value to separate the pure spectrum and calculate the concentration value, thereby obtaining the thermodynamic parameter, the pure spectrum, and the concentration value for each pure spectrum according to the equilibrium model. Patent Document 6 describes "a reaction control system for an alkylene oxide addition reaction, comprising: a reactor having a stirrer; a calculation means for calculating at least one of the hydroxyl value and cloud point of the reaction product from the near-infrared absorption spectrum of the reaction solution during the reaction, either by providing a line to take a portion of the reaction solution from the reactor and return it to the reactor via a near-infrared absorption spectroscopy analysis means, or by providing a detection end of a near-infrared absorption spectroscopy analysis means directly into the reactor; and a means for controlling the amount of alkylene oxide supplied to the reactor according to the calculated value." (Claim 1) [Prior art document] [Patent] [Patent Document 1] Japanese Unexamined Patent Publication No. 2000-298512 [Patent Document 2] Japanese Unexamined Patent Publication No. 2001-318088 [Patent Document 3] Special Publication No. 2002-534674 [Patent Document 4] Japanese Unexamined Patent Publication No. 2019-211400 [Patent Document 5] Japanese Unexamined Patent Publication No. 2024-113582 [Patent Document 6] Japanese Unexamined Patent Publication No. 2000-1451 [Overview of the project]

[0003] In a first aspect of the present invention, an analytical device is provided for estimating the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown. The analytical device comprises a spectrum acquisition unit, a calculation unit, and an estimation unit. The spectrum acquisition unit may acquire spectral spectra of the chemical reaction system at multiple time points. The calculation unit may calculate characteristic quantities of the spectral spectra at each time point from the spectral spectra at multiple time points. The estimation unit may estimate the endpoint of the chemical reaction based on the changes in the characteristic quantities calculated by the calculation unit.

[0004] In the above, the analytical apparatus further comprises a specification unit. The specification unit may identify the amount of a raw material of unknown concentration, which is a raw material of unknown concentration used in the chemical reaction system, based on the endpoint of the chemical reaction estimated by the estimation unit.

[0005] In the above, the raw material with an unknown concentration may be the product of a chemical reaction preceding the chemical reaction being estimated.

[0006] In the above, the calculation unit may calculate the principal components of the spectral spectrum at each of the multiple time points as features by performing principal component analysis on the spectral spectra at multiple time points.

[0007] In the above, the calculation unit may calculate features based on the peak area and / or peak intensity of a specific wavelength included in the spectral spectrum at each of the multiple time points.

[0008] In the above, the estimation unit may estimate the endpoint of the chemical reaction based on the first derivative of the feature with respect to the passage of time.

[0009] In the above, the estimation unit may estimate the point in time when the absolute value of the first derivative of the feature with respect to the passage of time becomes greater than or equal to a threshold as the endpoint of the chemical reaction.

[0010] In the above, the analytical apparatus further comprises a preprocessing unit for preprocessing the spectral data. The calculation unit may calculate feature quantities from the spectral data preprocessed by the preprocessing unit.

[0011] In the above, the preprocessing unit may apply one or more of the following to the spectral spectrum as preprocessing: baseline correction, first derivative, and second derivative.

[0012] In the above, the chemical reaction may be part of a continuous reaction in which the product is used as a new raw material for the next reaction.

[0013] In the above, the chemical reaction may be a reaction in which a second monomer different from the first monomer is polymerized onto a polymer consisting of repeating first monomers to produce a block copolymer.

[0014] In a second aspect of the present invention, there is provided an analysis method for estimating the end point of a chemical reaction in which the concentration of at least one raw material is unknown. The analysis method includes a spectrum acquisition step, a calculation step, and an estimation step. In the spectrum acquisition step, spectral spectra at a plurality of time points in the chemical reaction system may be acquired. In the calculation step, a feature amount of the spectral spectrum at each time point may be calculated from the spectral spectra at the plurality of time points. In the estimation step, the end point of the chemical reaction may be estimated based on the change in the feature amount calculated in the calculation step.

[0015] In a third aspect of the present invention, there is provided a program for estimating the end point of a chemical reaction in which the concentration of at least one raw material is unknown. The program is executed by a computer and causes the computer to function as a spectrum acquisition unit, a calculation unit, and an estimation unit. The spectrum acquisition unit may acquire spectral spectra at a plurality of time points in the chemical reaction system. The calculation unit may calculate a feature amount of the spectral spectrum at each time point from the spectral spectra at the plurality of time points. The estimation unit may estimate the end point of the chemical reaction based on the change in the feature amount calculated by the calculation unit.

[0016] Note that the above summary of the invention does not list all the features of the present invention. Also, sub-combinations of these feature groups can also be inventions.

Brief Description of the Drawings

[0017] [Figure 1] An example of a continuous reaction according to this embodiment is shown. [Figure 2] An example of the configuration of the analyzer 50 according to this embodiment is shown. [Figure 3] An example of the flow of the analysis method according to this embodiment is shown. [Figure 4] An example of the sub-flow of S300 of the flow according to FIG. 3 is shown. [Figure 5] An example of a chemical reaction targeted by this embodiment is shown. [Figure 6] An example of a graph of the feature amount according to this embodiment is shown. [Figure 7]Another example of a feature graph according to this embodiment is shown. [Figure 8] Examples of a computer 2200 in which multiple aspects of the present invention may be embodied in whole or in part are shown. [Modes for carrying out the invention]

[0018] The present invention will be described below through embodiments of the invention, but these embodiments are not intended to limit the invention as defined in the claims. Furthermore, not all combinations of features described in the embodiments are necessarily essential to the solution of the invention.

[0019] Figure 1 shows an example of a continuous reaction according to this embodiment. Figure 1 is an example of a reaction to produce a product 30 having structures derived from multiple raw materials A, B, C...Z. First, in the first reaction stage, raw material A10 is reacted with raw material B12 to obtain intermediate AB14. Next, in the second reaction stage, intermediate AB14 is reacted with raw material C16 to obtain intermediate ABC18. In the third and subsequent reactions, raw material D20 and the like are similarly reacted with the intermediates one after another to continue the reaction, and finally a product 30 (ABCD...Z) having structures derived from raw materials A, B, C, D...Z is obtained. Such a reaction can be carried out even in large-scale plants.

[0020] Here, the concentrations and amounts of the reaction raw materials (e.g., raw material A10, raw material B12, raw material C16, raw material D20, etc.) are known, but the concentrations of the intermediates (e.g., intermediate AB14, intermediate ABC18, etc.) are not necessarily clear, as they depend on the progress of the forward and side reactions at each stage and / or the yield of purification. A calibration curve is necessary to accurately measure the concentration of the intermediates. To obtain a calibration curve, it is necessary to obtain a sample of the purified intermediate beforehand, generate standard samples of multiple concentrations based on this sample, and analyze them using HPLC or similar methods.

[0021] However, this method not only requires time and cost for purifying the intermediate and creating a calibration curve, but it also makes it difficult to grasp the progress of the reaction (for example, the degree of raw material consumption or the endpoint of the chemical reaction) by measuring the amount of the intermediate in real time during the reaction. On the other hand, the analytical apparatus 50 according to this embodiment, which will be described later, makes it possible to grasp the progress of the reaction, the amount of intermediate produced, etc. in real time.

[0022] Figure 2 shows an example of the configuration of the analytical apparatus 50 according to this embodiment. The analytical apparatus 50 in this embodiment analyzes the progress of a chemical reaction in real time. For example, the analytical apparatus 50 estimates the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown. For example, the chemical reaction may be part of a continuous reaction in which the product is used as a new raw material to carry out the next reaction. The analytical apparatus 50 comprises a reaction unit 100 and a calculation unit 200.

[0023] The reaction unit 100 houses the raw materials and products, and the chemical reaction to be analyzed is carried out there. The reaction unit 100 may have the configuration of a known reactor. For example, the reaction unit 100 may have a reaction vessel 110, a raw material supply unit 120, a stirrer 130, and a spectroscopic sensor 140.

[0024] The reaction vessel 110 provides a space in which the chemical reaction is carried out. The reaction vessel 110 may be a known reaction vessel. The reaction vessel 110 may have a volume and shape appropriate to the scale of the reaction being carried out. For example, the reaction vessel 110 may be substantially cylindrical.

[0025] The raw material supply unit 120 supplies the materials necessary for the reaction to the reaction vessel 110. For example, the raw material supply unit 120 supplies the reaction raw materials, catalyst, solvent, or mixtures thereof to the reaction vessel 110. The raw material supply unit 120 may be implemented using a known configuration such as a tank and a pump. The raw material supply unit 120 is controlled by the calculation unit 200. The raw material supply unit 120 may include a metering pump.

[0026] The agitator 130 stirs the fluid (also called the "chemical reaction system") containing reactants and products present in the reaction vessel 110. The agitator 130 may include rotating impellers. The material and shape of the impellers may be selected according to the viscosity and reactivity of the chemical reaction system.

[0027] The spectroscopic sensor 140 acquires the spectral spectrum of the chemical reaction system. In particular, the spectroscopic sensor 140 may be an in-line spectroscopic measuring device capable of real-time measurement. The spectroscopic sensor 140 may acquire known spectra, for example, ultraviolet-visible absorption spectra, near-infrared absorption spectra, infrared absorption spectra, or Raman spectra. The spectroscopic sensor 140 supplies the measurement results to the calculation unit 200. A light source corresponding to the target wavelength of the spectroscopic sensor 140 may be separately provided in the reaction unit 100.

[0028] In addition to the above, the reaction unit 100 may have other elements necessary for controlling the reaction. For example, the reaction unit 100 may have an exposure device, a cooling device, a heating device, a reflux device, and / or baffles, etc., as needed.

[0029] When dealing with a continuous reaction, multiple reaction units 100 may be provided. In this case, the product or its purified product stored in the reaction unit 100 that carried out the first reaction may be supplied via piping or the like to another reaction unit 100 that carries out a second reaction following the first reaction.

[0030] The analytical device 50 does not necessarily have to include a reaction unit 100. In this case, the analytical device 50 may communicate with an external reactor equivalent to the reaction unit 100, control the reaction of the external reactor, and acquire data from the external reactor.

[0031] The calculation unit 200 acquires data measured in the reaction unit 100 and controls the reaction in the reaction unit 100. The calculation unit 200 may include a reaction control unit 210, a spectrum acquisition unit 220, a preprocessing unit 225, a calculation unit 230, an estimation unit 240, and a specific unit 250.

[0032] The arithmetic unit 200 may be a computer such as a PC (personal computer), tablet computer, smartphone, workstation, server computer, or general-purpose computer, and may also be a computer system in which multiple computers are connected.

[0033] Alternatively, the calculation unit 200 may be a dedicated computer designed for chemical reaction analysis, or dedicated hardware implemented by a dedicated circuit. The calculation unit 200 may be implemented by a single device (computer), or by multiple devices with assigned roles. In the calculation unit 200, although not specifically described below, memory / hard disk, etc., is provided, and information necessary for processing is stored as appropriate, and information is transmitted between each processing module such as the calculation unit 230 and the estimation unit 240.

[0034] The reaction control unit 210 controls the operation of the raw material supply unit 120 to supply the raw materials for the chemical reaction to the reaction vessel 110. For example, the reaction control unit 210 supplies a desired amount of raw materials to the reaction vessel 110 by controlling the operation of the pump of the raw material supply unit 120. The reaction control unit 210 may also control the supply of other materials (e.g., catalysts and / or solvents) that are directly or indirectly necessary for the chemical reaction, instead of the raw materials for the chemical reaction.

[0035] When dealing with a continuous reaction, the reaction control unit 210 may control the movement of the product or its purified product between multiple reaction units 100. For example, the reaction control unit 210 may use a pump or the like to supply the product or its purified product stored in the reaction unit 100 that carried out the first reaction to another reaction unit 100 that carries out a second reaction following the first reaction, via piping or the like.

[0036] The spectrum acquisition unit 220 acquires spectral data at multiple time points in the chemical reaction system. The spectrum acquisition unit 220 may continuously acquire spectral data from the spectral sensor 140.

[0037] The preprocessing unit 225 preprocesses the spectral spectrum acquired by the spectral acquisition unit 220. As part of the preprocessing, the preprocessing unit 225 may apply one or more of the following to the spectral spectrum: baseline correction, first derivative, and second derivative.

[0038] The calculation unit 230 calculates feature quantities of the spectral spectrum at each time point from the spectral spectra at multiple time points. For example, the calculation unit 230 may calculate the principal components of the spectral spectrum at each time point included in the multiple time points as feature quantities by performing principal component analysis on the spectral spectra at multiple time points. The calculation unit 230 may calculate feature quantities from spectral spectra preprocessed by the preprocessing unit 225, or from spectral spectra acquired by the spectrum acquisition unit 220.

[0039] The estimation unit 240 estimates the endpoint of the chemical reaction based on the changes in the feature quantities calculated by the calculation unit 230. The estimation unit 240 may also estimate the endpoint of the chemical reaction based on the nth derivative (where n is a natural number) of the feature quantity with respect to the passage of time.

[0040] The identification unit 250 identifies the amount of raw materials with unknown concentrations used in the chemical reaction system, based on the endpoint of the chemical reaction estimated by the estimation unit 240. For example, the identification unit 250 may identify the amount of raw materials with unknown concentrations based on the total amount of raw materials with known concentrations used up to the endpoint of the chemical reaction and stoichiometry. For example, the identification unit 250 may identify the initial concentration of an intermediate or the amount of intermediate used in a continuous reaction.

[0041] Thus, the analytical apparatus 50 of this embodiment can analyze the degree of progress of a chemical reaction and the endpoint of a chemical reaction in real time by using a spectral distribution. Furthermore, according to this embodiment, the time and cost of analysis can be reduced compared to methods using calibration curves, etc.

[0042] Figure 3 shows an example of the flow of the analysis method according to this embodiment. The analyzer 50 analyzes the chemical reaction by performing, for example, the processes S100 to S700. The order of the processes S100 to S700 may be changed, and some processes may be omitted.

[0043] First, in S100, the chemical reaction to be analyzed is started. The reaction may be started by supplying the materials necessary for the chemical reaction (e.g., raw materials, catalyst, and / or solvent) to the reaction vessel 110. The supply of materials may be controlled by the reaction control unit 210 controlling the raw material supply unit 120. Alternatively, the materials may be supplied by means other than the raw material supply unit 120. Some of the materials may be supplied to the reaction vessel 110 in advance.

[0044] In the case of a continuous reaction, the reaction vessel 110 may use at least part of the product from the previous reaction as the raw material (so-called intermediate) for the next reaction. Alternatively, the intermediate may be supplied to the reaction vessel 110 from another reaction vessel where the previous reaction took place, via piping or the like.

[0045] For example, in the continuous reaction shown in Figure 1, if raw material A has been supplied to the reaction vessel 110 in advance, the reaction control unit 210 may supply raw material B to the reaction vessel 110 from the raw material supply unit 120 after the reaction starts in S100. After the reaction starts in S100, the reaction control unit 210 may have all the raw materials (for example, raw materials A and B) supplied to the reaction vessel 110 from the raw material supply unit 120. In the second stage of the reaction, the reaction control unit 210 may supply raw material C to the reaction vessel 110, which already contains the intermediate AB, the product of the first stage of the reaction, from the raw material supply unit 120.

[0046] The reaction control unit 210 may control the raw material supply unit 120 to control the amount of raw materials supplied. For example, the reaction control unit 210 may control the raw material supply unit 120 so that a fixed volume (e.g., 1 ml, 10 ml, 100 ml, etc.) or fixed weight (e.g., 1 g, 10 g, 100 g, etc.) of raw material (e.g., raw material B in the first stage reaction in Figure 1, or raw material C in the second stage reaction) is supplied every hour (e.g., every second or every minute). For example, the reaction control unit 210 may control the supply amount by commanding the raw material supply unit 120, which is a quantitative supply pump, to supply a certain amount and / or supply time per hour.

[0047] The reaction unit 100 may initiate and / or accelerate the chemical reaction by applying heat or light to the chemical reaction system as needed. The reaction unit 100 may also accelerate the chemical reaction by stirring the chemical reaction system with the stirrer 130 during the reaction. For example, the reaction control unit 210 may control the initiation and / or acceleration of the chemical reaction by controlling the stirrer 130, heating device, and / or exposure device of the reaction unit 100.

[0048] Next, in S200, the analyzer 50 acquires spectral spectra of the chemical reaction system at multiple time points. The spectrum acquisition unit 220 acquires data of the spectral spectrum of the chemical reaction system after the start of the reaction from the spectral sensor 140. The spectrum acquisition unit 220 may acquire spectral spectra at multiple time points. The spectrum acquisition unit 220 may acquire spectral spectra of the reaction in real time, one after the other. The spectrum acquisition unit 220 supplies the spectral spectra to the calculation unit 200.

[0049] Next, in S300, the analyzer 50 calculates feature quantities from the spectral data acquired in S200.

[0050] Figure 4 shows an example of a subflow of S300 in the flow shown in Figure 3. The preprocessing unit 225 and the calculation unit 230 may execute the process of S300 by executing the processes of S310 to S320. In addition to S310 to S320, other processes may be executed. Some of the processes of S310 to S320 may be omitted.

[0051] In S310, the preprocessing unit 225 preprocesses the spectral spectrum acquired by the spectrum acquisition unit 220 in S200. The preprocessing unit 225 may use known preprocessing techniques for spectral spectra. For example, the preprocessing unit 225 may perform standardization, normalization, removal of pre-defined solvent components, baseline correction, first derivative, second derivative, or a combination thereof for each of the spectral spectra at multiple time points. As an example, the preprocessing unit 225 may perform baseline correction on the spectral spectrum at each time point.

[0052] Next, in S320, the calculation unit 230 calculates the feature quantities of the spectral spectrum at each time point by quantifying the features of the spectral spectrum that were preprocessed in S310. As a result, the calculation unit 230 outputs the feature quantities at each time point in time when the spectral spectrum was acquired.

[0053] For example, the calculation unit 230 may perform principal component analysis (PCA) on the spectral spectra at multiple time points to calculate the scores obtained as the principal components of the spectral spectra at each time point included in the multiple time points as features. As an example, the calculation unit 230 may calculate the first principal component in the principal component analysis as a feature.

[0054] The calculation unit 230 may perform principal component analysis using all of the spectral spectra obtained at multiple time points from the start of the reaction up to the present time. Alternatively, the calculation unit 230 may perform principal component analysis using spectral spectra at multiple time points from the present time up to a predetermined time (for example, 360 spectral spectra at 10-second intervals from 60 minutes ago to the present time).

[0055] The calculation unit 230 may identify the wavelength range in which changes occur in the spectral spectrum due to a chemical reaction and set the identified wavelength range as the wavelength range to be analyzed for principal component analysis. The calculation unit 230 may also receive input from the user regarding the target wavelength range during principal component analysis. In addition to / or instead of principal component analysis, the calculation unit 230 may apply independent component analysis (ICA) and / or multivariate spectral decomposition (MCR) to the spectral spectrum to calculate feature quantities.

[0056] The calculation unit 230 may calculate the characteristic quantities of the spectral spectrum at each time point based on the peak shape of the spectral spectrum, instead of using principal component analysis or the like. For example, the calculation unit 230 may calculate the characteristic quantities based on the peak area and / or peak intensity of a specific wavelength included in the spectral spectrum at each of the multiple time points.

[0057] In S400, following S300, the estimation unit 240 estimates the endpoint of the chemical reaction based on the changes in the feature quantities calculated in S300. The estimation unit 240 may detect the endpoint of the chemical reaction and determine that the chemical reaction has ended if the changes in the feature quantities satisfy predetermined conditions. The estimation unit 240 may determine that the chemical reaction is continuing if the changes in the feature quantities do not satisfy predetermined conditions.

[0058] The estimation unit 240 may estimate the endpoint of the chemical reaction based on the numerical value of the feature with respect to the passage of time, or on the nth derivative of the feature (where n is a natural number). For example, the estimation unit 240 may calculate the first or second derivative of the feature with respect to the passage of time.

[0059] The estimation unit 240 may estimate the endpoint of a chemical reaction by comparing a feature or a numerical value based on a feature with a threshold. For example, the estimation unit 240 may estimate the endpoint of a chemical reaction based on whether the feature or a numerical value based on a feature is greater than or equal to a threshold, or less than or equal to a threshold. For example, the estimation unit 240 may estimate the endpoint of a chemical reaction based on whether the feature or a numerical value based on a feature is within a predetermined range.

[0060] For example, the estimation unit 240 may estimate the point in time when the absolute value of the feature's derivative (e.g., the first derivative) with respect to time exceeds a threshold as the endpoint of the chemical reaction. For example, the estimation unit 240 may estimate the point in time when the absolute value of the feature falls below a threshold as the endpoint of the chemical reaction. Specific examples of processing by the estimation unit 240 will be described later.

[0061] Next, in S500, the estimation unit 240 determines whether the chemical reaction has finished at this point. If the estimation unit 240 determines that the chemical reaction has finished in S400, the analyzer 50 proceeds to S600. Otherwise, the analyzer 50 continues the chemical reaction and continues acquiring the spectral data in S200.

[0062] If the chemical reaction continues, the analyzer 50 may wait for a predetermined time (e.g., 1 to 300 seconds) before resuming the S200 process. For example, the S200 process may be resumed so that the acquisition of the spectral data of S200 occurs at regular intervals (e.g., 1 to 300-second intervals). This is because reacquiring the spectral data after a very short time may not yield any noticeable changes, potentially wasting memory and / or computing resources.

[0063] If the estimation unit 240 determines that the chemical reaction has finished at this point, it may, if necessary, sample the chemical reaction system and analyze it using HPLC or the like to confirm whether the raw material of unknown concentration (e.g., intermediate AB) has disappeared. If the raw material of unknown concentration (e.g., intermediate AB) has not disappeared, the process of S200 may be continued.

[0064] The processes in S200 to S500 do not necessarily have to be executed sequentially; they may be executed concurrently.

[0065] In step S600, the reaction control unit 210 controls the operation of the raw material supply unit 120 to stop the supply of raw materials for the chemical reaction. For example, in the first stage of the reaction in Figure 1, the supply of raw material B may be stopped, and in the second stage of the reaction, the supply of raw material C may be stopped. In addition to stopping the supply of raw materials, the reaction control unit 210 may also control the temperature (e.g., cooling or heating) and / or add a reaction terminating agent. This makes it possible to save the use of raw materials and other resources that do not contribute to the chemical reaction.

[0066] Next, in S700, the identification unit 250 identifies the amount of the raw material with an unknown concentration, which is a raw material whose concentration is unknown and was used in the chemical reaction system, based on the endpoint of the chemical reaction estimated in S400. The identification unit 250 identifies the amount and concentration of the raw material with an unknown concentration, as well as the amount of the product, based on the total amount of raw materials with known concentrations added from the start of the reaction to the endpoint of the reaction and the stoichiometry of the chemical reaction. The raw material with an unknown concentration may be the product of a chemical reaction preceding the chemical reaction being estimated (for example, intermediate AB, which is the product of the first reaction in Figure 1 and one of the raw materials for the second reaction).

[0067] In the stoichiometry of chemical reactions, the molar amount consumed by a raw material of known concentration x is given by the molar amount consumed by a raw material of unknown concentration y (let's call y=mx) and the molar amount of product formed z (let's call z=nx). Here, m and n are the molar ratios of the chemical reaction based on stoichiometry. If the concentration of the raw material of known concentration is M X Let the total amount be X. The concentration of the raw material with an unknown concentration is M. Y Let Y be the total amount (initial amount). Let Z be the amount of product produced.

[0068] In this case, the specific part 250 is, for example, y=(M X By calculating ×X)×(mx / x), the initial (consumed) molar amount y of the raw material with unknown concentration is determined, M Y =(M X The concentration M of the raw material with an unknown concentration can be calculated by calculating ×X)×(mx / x)×(1 / Y). Y The identifying part 250 can identify z=(M X By calculating ×X)×(nx / x), the molar amount z of the product (intermediate in the next chemical reaction) can be determined.

[0069] FIG. 5 shows an example of a chemical reaction targeted in the present embodiment. The analyzer 50 according to the present embodiment may be used, for example, in a peptide synthesis reaction as shown in FIG. 5. R, R', and R" of the compounds in the figure may be any organic group. For example, R may be any functional group (side chain), R' may be a protecting group, and R" may be a peptide or an amino acid constituting an intermediate. The second-stage reaction in FIG. 1 may be a reaction in which raw material C is reacted with intermediate AB as shown in FIG. 5 to produce intermediate ABC. Here, the concentration of raw material C is known.

[0070] In the reaction shown in FIG. 5, the molar ratio of raw material C consumed in the reaction, intermediate AB, and intermediate ABC produced is 1:1:1 (that is, x:y:z = 1:1:1). Therefore, the specifying unit 250 may calculate the total amount (for example, the weight or volume of raw material C) of raw material C, which is a raw material with a known concentration, introduced from the start to the end of the reaction by multiplying the amount of raw material C introduced per unit time into the chemical reaction system by the time from the start to the end of the reaction.

[0071] The analysis method and analyzer of the present embodiment may be applied to various synthesis reactions other than the peptide synthesis reaction. The analysis method and analyzer of the present embodiment are particularly preferably used for chemical reactions in which the molar ratios of raw materials and products are known. For example, the analyzer and analysis method of the present embodiment may be used in a synthesis reaction of a compound in which a certain structure such as nucleic acid or polysaccharide is repeatedly included in addition to / instead of peptides. The analyzer and analysis method of the present embodiment may be applied to a single reaction containing a raw material with an unknown concentration, rather than a continuous reaction.

[0072] Next, the specifying unit 250 calculates the molar amount M of raw material C from the known concentration and total amount of raw material C (and the density of raw material C if necessary). C The specifying unit 250 calculates the molar amount M. C The same amount as M is specified as the consumption molar amount M of intermediate AB, which is a raw material with an unknown concentration, AB and the production molar amount M of intermediate ABC, which is a product. ABC can be specified.

[0073] Furthermore, the specifying unit 250 calculates the consumption molar amount M.AB The concentration of intermediate AB, which is a raw material with an unknown concentration, is determined before the reaction using the amount (volume or weight) of intermediate AB added. The identification unit 250 determines the amount (volume or weight, etc.) of the product before and / or after purification, and the molar amount M produced. ABC The concentration (volume concentration or weight concentration, etc.) of the intermediate ABC, which is the product, may be determined using this method. In this way, the identification unit 250 can determine the amount and concentration of unknown raw materials and products based on the endpoint of the chemical reaction and the ratio of raw materials and products in the chemical reaction.

[0074] The process may be terminated after S700, and instead, another reaction using the product as a starting material may be carried out. For example, the subsequent reaction in the sequence reaction shown in Figure 1 may be carried out. Before carrying out the subsequent reaction, the product may be separated, purified, transferred, and / or by-products and starting materials may be removed. The processes S100 to S700 may also be repeated in the subsequent reaction.

[0075] As described above, this embodiment allows for the real-time calculation of the concentration and quantity of raw materials with unknown concentrations by analyzing the spectral spectrum of a chemical reaction system, simultaneously estimating the progress of the chemical reaction and its endpoint. Furthermore, this embodiment allows for the rapid, low-cost, and short-time analysis of the progress of a chemical reaction compared to methods using calibration curves. In particular, this embodiment is more suitable for analyzing intermediates in continuous reactions where information on raw materials is difficult to obtain compared to batch synthesis of individual components.

[0076] Figure 6 shows an example of a feature graph according to this embodiment. The horizontal axis of Figure 6 represents the elapsed time (indicated as "reaction time (minutes)") after the start of the chemical reaction that produces intermediate ABC (second row in Figure 1). The vertical axis on the left of Figure 6 shows the change over time of the first principal component obtained by the calculation unit 230 performing principal component analysis on the spectral data at multiple time points, and corresponds to a downward sloping curve. The vertical axis on the right of Figure 6 represents the total amount of raw material C added to the chemical reaction system.

[0077] As shown in the figure, the value of the first principal component decreases immediately after the reaction and continues to decrease at a nearly constant rate until time point 620. The fact that the value of the first principal component changes at a constant rate indicates that the composition of the chemical reaction system also changes at a constant rate. This suggests that the chemical reaction proceeds at a nearly constant rate before time point 620.

[0078] At time point 620 (indicated as 22.4 min in the figure), the slope of the line segment representing the first principal component changes sharply to positive. This indicates that the reaction, which had been proceeding at a constant pace, suddenly underwent a change. In other words, the abrupt change in slope suggests that at time point 620, the raw materials other than raw material C (e.g., intermediate AB) were depleted, and the chemical reaction ceased to proceed.

[0079] At S400, immediately following time 620, the estimation unit 240 may detect such a change in the slope of the first principal component. The rapid change in the slope of the first principal component in Figure 6 is reflected in the value of the nth derivative (e.g., the first derivative) of the first principal component. For example, when the first principal component is used as a feature, the estimation unit 240 calculates the nth derivative (e.g., the first derivative) of the first principal component, and determines that the slope of the first principal component has changed rapidly (i.e., the chemical reaction has ended) when the nth derivative (or its absolute value) exceeds a threshold.

[0080] If the amount of raw material C added by time 620 is 1.7 mmol as shown in the figure, the identification unit 250 identifies the amount of intermediate AB that has reacted with raw material C as 1.7 mmol, the same as raw material C. The identification unit 250 also identifies the amount of the product intermediate ABC as 1.7 mmol.

[0081] On the other hand, as shown in the diagram, raw material C is continuously added from immediately after the start of the reaction, and the total amount added continues to increase. At time 610, the addition of raw material C is stopped. Since it is impossible to continue the chemical reaction at time 620, from time 620 to time 610, raw material C, which does not contribute to the reaction, was added unnecessarily.

[0082] The estimation unit 240 of this embodiment can determine in real time whether or not the chemical reaction has finished. Therefore, according to this embodiment, after time 620, the unnecessary supply of raw materials can be stopped immediately.

[0083] Figure 7 shows another example of a feature graph according to this embodiment. The horizontal axis of Figure 7 shows the elapsed time (indicated as "reaction time (minutes)") after the start of the chemical reaction that produces intermediate ABC (second row in Figure 1). The vertical axis of Figure 7 shows the peak area of ​​intermediate AB detected by analyzing the chemical reaction system with high-performance liquid chromatography (HPLC).

[0084] As shown in the figure, the peak area decreases immediately after the reaction and continues to decrease at a nearly constant rate until time point 710. The fact that the peak area decreases at a constant rate indicates that a specific component in the chemical reaction system also decreases at a constant rate. This suggests that, prior to time point 710, the consumption of unsupplied raw materials (e.g., intermediate AB) proceeds at a nearly constant rate.

[0085] When time point 710 (plotted around 25 minutes in the figure) is reached, the decrease in the peak area value stops. This indicates that the raw materials other than raw material C (e.g., intermediate AB) have been depleted and the reaction has stopped. If the calculation unit 230 uses the peak area in the wavelength range corresponding to intermediate AB in the spectral spectrum as a feature, the change in this feature over time is expected to show a similar trend to the graph in Figure 7.

[0086] In S400, the estimation unit 240 may detect a change in the peak area of ​​the spectral spectrum. The flattening of the slope of the peak area of ​​the spectral spectrum is reflected in the numerical value of the peak area itself, and / or the nth derivative (e.g., the first derivative) of the peak area.

[0087] For example, when using peak area as a feature, the estimation unit 240 determines that the chemical reaction has ended when the value of the peak area falls below a threshold set to be close to 0. Alternatively, the estimation unit 240 may determine that the chemical reaction has ended when the nth-order (e.g., first-order) derivative (or its absolute value) of the peak area exceeds a threshold.

[0088] The calculation unit 230 may use the peak intensity of a specific wavelength range as a feature quantity in addition to / or instead of the peak area of ​​a specific wavelength range. The calculation unit 230 may use the peak area and / or peak intensity corresponding to a single peak, or alternatively, it may use the peak area and / or peak intensity corresponding to multiple peaks.

[0089] Various embodiments of the present invention may be described with reference to flowcharts and block diagrams, where a block may represent (1) a stage in a process in which an operation is performed or (2) a section of a device having the role of performing the operation. Specific stages and sections may be implemented by dedicated circuits, programmable circuits supplied with computer-readable instructions stored on a computer-readable medium, and / or processors supplied with computer-readable instructions stored on a computer-readable medium. Dedicated circuits may include digital and / or analog hardware circuits, and may include integrated circuits (ICs) and / or discrete circuits. Programmable circuits may include reconfigurable hardware circuits, including logical AND, logical OR, logical XOR, logical NAND, logical NOR, and other logic operations, flip-flops, registers, memory elements such as field-programmable gate arrays (FPGAs), programmable logic arrays (PLAs), etc.

[0090] Computer-readable media may include any tangible device capable of storing instructions to be executed by a suitable device, and as a result, computer-readable media having instructions stored therein will comprise a product containing instructions that can be executed to create means for performing operations specified in a flowchart or block diagram. Examples of computer-readable media may include electronic storage media, magnetic storage media, optical storage media, electromagnetic storage media, semiconductor storage media, etc. More specific examples of computer-readable media may include floppy disks, diskettes, hard disks, random access memory (RAM), read-only memory (ROM), erasable programmable read-only memory (EPROM or flash memory), electrically erasable programmable read-only memory (EEPROM), static random access memory (SRAM), compact disk read-only memory (CD-ROM), digital multipurpose disc (DVD), Blu-ray® disc, memory stick, integrated circuit card, etc.

[0091] Computer-readable instructions may include assembler instructions, instruction set architecture (ISA) instructions, machine instructions, machine-dependent instructions, microcode, firmware instructions, state setting data, or source code or object code written in any combination of one or more programming languages, including object-oriented programming languages ​​such as Smalltalk®, Java®, C++, and traditional procedural programming languages ​​such as the C programming language or similar programming languages.

[0092] Computer-readable instructions may be provided locally or via a wide area network (WAN) such as a local area network (LAN) or the internet to the processor or programmable circuit of a programmable data processing device such as a general-purpose computer, a special-purpose computer, or another computer, and the computer-readable instructions may be executed to create means for performing operations specified in a flowchart or block diagram. Examples of processors include computer processors, processing units, microprocessors, digital signal processors, controllers, microcontrollers, etc.

[0093] Figure 8 shows an example of a computer 2200 in which multiple aspects of the present invention may be embodied in whole or in part. A program installed on the computer 2200 can cause the computer 2200 to function as an operation or one or more sections of an apparatus according to an embodiment of the present invention, or to execute such operation or one or more sections, and / or to cause the computer 2200 to execute a process or a stage of such process according to an embodiment of the present invention. Such a program may be executed by the CPU 2212 to cause the computer 2200 to perform a particular operation associated with some or all of the blocks in the flowcharts and block diagrams described herein.

[0094] The computer 2200 according to this embodiment includes a CPU 2212, RAM 2214, a graphics controller 2216, and a display device 2218, which are interconnected by a host controller 2210. The computer 2200 also includes input / output units such as a communication interface 2222, a hard disk drive 2224, a DVD-ROM drive 2226, and an IC card drive, which are connected to the host controller 2210 via an input / output controller 2220. The computer also includes legacy input / output units such as a ROM 2230 and a keyboard 2242, which are connected to the input / output controller 2220 via an input / output chip 2240.

[0095] The CPU 2212 operates according to programs stored in the ROM 2230 and RAM 2214, thereby controlling each unit. The graphics controller 2216 retrieves image data generated by the CPU 2212 from a frame buffer provided in RAM 2214 or from itself, and displays the image data on the display device 2218.

[0096] The communication interface 2222 communicates with other electronic devices via a network. The hard disk drive 2224 stores programs and data used by the CPU 2212 in the computer 2200. The DVD-ROM drive 2226 reads programs or data from the DVD-ROM 2201 and provides them to the hard disk drive 2224 via the RAM 2214. The IC card drive reads programs and data from the IC card and / or writes programs and data to the IC card.

[0097] The ROM 2230 stores boot programs and / or programs that depend on the computer 2200's hardware, which are executed by the computer 2200 when activated. The input / output chip 2240 may also connect various input / output units to the input / output controller 2220 via parallel ports, serial ports, keyboard ports, mouse ports, etc.

[0098] The program is provided on a computer-readable medium such as a DVD-ROM 2201 or an IC card. The program is read from the computer-readable medium and installed on a hard disk drive 2224, RAM 2214, or ROM 2230, which are also examples of computer-readable medium, and executed by the CPU 2212. The information processing described within these programs is read by the computer 2200, resulting in coordination between the program and the various types of hardware resources described above. The apparatus or method may be configured to realize the manipulation or processing of information in accordance with the use of the computer 2200.

[0099] For example, when communication is performed between a computer 2200 and an external device, the CPU 2212 may execute a communication program loaded into RAM 2214 and, based on the processing described in the communication program, instruct the communication interface 2222 to perform communication processing. Under the control of the CPU 2212, the communication interface 2222 reads transmission data stored in a transmission buffer processing area provided in a recording medium such as RAM 2214, a hard disk drive 2224, a DVD-ROM 2201, or an IC card, transmits the read transmission data to the network, or writes received data received from the network to a reception buffer processing area provided on the recording medium.

[0100] The CPU 2212 reads all or necessary parts of a file or database stored on an external storage medium such as a hard disk drive 2224, a DVD-ROM drive 2226 (DVD-ROM 2201), or an IC card into the RAM 2214, and may perform various types of processing on the data in the RAM 2214. The CPU 2212 then writes the processed data back to the external storage medium.

[0101] Various types of information, such as various types of programs, data, tables, and databases, may be stored on the recording medium and subjected to information processing. The CPU 2212 may perform various types of processing on the data read from RAM 2214, including various types of operations, information processing, conditional judgments, conditional branching, unconditional branching, information retrieval / replacement, etc., as described throughout this disclosure and specified by the program instruction sequence, and write the results back to RAM 2214. The CPU 2212 may also retrieve information in files, databases, etc., within the recording medium. For example, if multiple entries are stored in the recording medium, each having an attribute value of a first attribute associated with an attribute value of a second attribute, the CPU 2212 may search among the multiple entries for an entry that matches the condition for which the attribute value of the first attribute is specified, read the attribute value of the second attribute stored in that entry, and thereby obtain the attribute value of the second attribute associated with the first attribute that satisfies a predetermined condition.

[0102] The programs or software modules described above may be stored on or near computer 2200 on a computer-readable medium. Alternatively, recording media such as hard disks or RAM provided within a server system connected to a dedicated communication network or the Internet can be used as computer-readable media, thereby providing programs to computer 2200 via the network.

[0103] Although the present invention has been described above using embodiments, the technical scope of the present invention is not limited to the scope described in the above embodiments. It will be apparent to those skilled in the art that various modifications or improvements can be made to the above embodiments. It will be clear from the claims that such modified or improved forms may also be included in the technical scope of the present invention.

[0104] It should be noted that the execution order of operations, procedures, steps, and stages in the apparatus, systems, programs, and methods shown in the claims, specifications, and drawings is not explicitly stated as "before," "prior to," etc., and can be implemented in any order unless the output of a previous process is used in a later process. Even if the operation flow in the claims, specifications, and drawings is described using phrases such as "first," "next," etc. for convenience, it does not mean that it is essential to perform them in that order. The notation "A and / or B" may mean "A, B, or A and C." The notation "A, B and / or C" may mean "any one of A, B, and C, or any combination of two or more of these." [Explanation of Symbols]

[0105] 10 Raw material A 12 Raw material B 14 Intermediate AB 16 Raw material C 18 Intermediate ABC 20 Raw material D 30 products 50 Analyzer 100 reaction section 110 reaction vessels 120 Raw material supply department 130 Agitator 140 Spectroscopic Sensor 200 Arithmetic section 210 Reaction Control Unit 220 Spectrum Acquisition Unit 225 Pre-processing section 230 Calculation Unit 240 Estimation part 250 Specific section As of 610 As of 620 As of 710 2200 Computers 2201 DVD-ROM 2210 Host Controller 2212 CPU 2214 RAM 2216 Graphics Controller 2218 Display Devices 2220 Input / Output Controller 2222 Communication Interface 2224 Hard Disk Drive 2226 DVD-ROM drive 2230 ROM 2240 Input / Output Chip 2242 keyboard

Claims

1. An analytical device for estimating the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown, A spectral acquisition unit that acquires spectral data of a chemical reaction system at multiple time points, A calculation unit that calculates characteristic quantities of the spectral spectrum at each time point from the spectral spectra at multiple time points, Based on the changes in the feature quantities calculated by the calculation unit, an estimation unit estimates the endpoint of the chemical reaction. An analytical device equipped with the following features.

2. The system further includes a specification unit that identifies the amount of a raw material of unknown concentration used in the chemical reaction system, based on the endpoint of the chemical reaction estimated by the estimation unit. The analytical apparatus according to claim 1.

3. The raw material of unknown concentration is a product of a chemical reaction preceding the chemical reaction being estimated. The analytical apparatus according to claim 2.

4. The calculation unit performs principal component analysis on the spectral spectra at the multiple time points to calculate the principal components of the spectral spectra at each of the multiple time points as the feature quantities. The analytical apparatus according to claim 1.

5. The calculation unit calculates the characteristic quantity based on the peak area and / or peak intensity of a specific wavelength included in the spectral spectrum at each of the multiple time points. The analytical apparatus according to claim 1.

6. The estimation unit estimates the endpoint of the chemical reaction based on the first derivative of the feature quantity with respect to the passage of time. The analytical apparatus according to claim 1.

7. The estimation unit estimates the point in time when the absolute value of the first derivative of the feature with respect to the passage of time becomes greater than or equal to a threshold as the endpoint of the chemical reaction. The analytical apparatus according to claim 1.

8. The system further comprises a preprocessing unit for preprocessing the aforementioned spectral spectrum, The calculation unit calculates the feature quantity from the spectral spectrum preprocessed by the preprocessing unit. The analytical apparatus according to claim 1.

9. The preprocessing unit applies one or more of the following to the spectral spectrum as preprocessing: baseline correction, first derivative, and second derivative. The analytical apparatus according to claim 8.

10. The aforementioned chemical reaction is part of a continuous reaction in which the product is used as a new raw material for the next reaction. The analytical apparatus according to claim 1.

11. The aforementioned chemical reaction is a reaction in which a second monomer, different from the first monomer, is polymerized onto a polymer consisting of repeating first monomers to produce a block copolymer. The analytical apparatus according to claim 1.

12. An analytical method for estimating the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown, The spectrum acquisition step involves obtaining spectral spectra of the chemical reaction system at multiple time points, A calculation step in which the characteristic quantities of the spectral spectrum at each time point are calculated from the spectral spectra at multiple time points, Based on the changes in the feature quantities calculated in the calculation step, an estimation step is performed to estimate the endpoint of the chemical reaction. An analytical method that includes the following features.

13. A program for estimating the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown, It is executed by a computer, and the computer, A spectral acquisition unit that acquires spectral data of a chemical reaction system at multiple time points, A calculation unit that calculates characteristic quantities of the spectral spectrum at each time point from the spectral spectra at multiple time points, Based on the changes in the feature quantities calculated by the calculation unit, an estimation unit estimates the endpoint of the chemical reaction. A program that makes it function as such.

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