WO2025063199A1 - Separation and purification method for medium-sized molecule pharmaceutical and separation and purification system for medium-sized molecule pharmaceutical - Google Patents

Abstract

The present invention provides a separation and purification method and a separation and purification system that make it possible to purify a highly pure medium-sized molecule pharmaceutical with a high yield, even when applied to production on a large scale.　A separation and purification method for icatibant according to one embodiment comprises: a primary processing step for supplying a processing target liquid containing icatibant and a plurality of impurities to a column which has been filled with a separation agent X, thereby obtaining a primary processing liquid in which an α component has been removed from the processing target liquid; and a secondary processing step for supplying the primary processing liquid to a plurality of filling parts which have been filled with a separation agent Y, thereby performing a simulated moving bed method for continuously separating the icatibant.　The α component is an impurity among the plurality of impurities in the processing target liquid which, in a chromatogram of the processing target liquid obtained in the primary processing step, has the smallest overlap with the peak area of the icatibant.

Description

Method for separating and purifying medium-molecule drugs and system for separating and purifying medium-molecule drugs

The present invention relates to a method for separating and purifying a medium-sized molecule drug and a system for separating and purifying a medium-sized molecule drug.
This application claims priority based on Japanese Patent Application No. 2023-152292, filed with the Japan Patent Office on September 20, 2023, the contents of which are incorporated herein by reference.

Medium molecule drugs are drugs that contain compounds with a molecular weight of 500 to 10,000, and are positioned between small molecule drugs and large molecule drugs. Medium molecule drugs usually include peptide drugs and nucleic acid drugs.
Peptide drugs are drugs whose main ingredient is a peptide with multiple amino acid residues. Among the many peptide drugs, next-generation peptide drugs with non-natural amino acid residues include glucagon-like peptide 1 (GLP-1) such as tirzepatide and icatibant.

Icatibant is a peptide consisting of a 10 amino acid sequence. It is a specific antagonist of the bradykinin B2 receptor and is therefore used to treat attacks of hereditary angioedema (HAE).
Icatibant is synthesized by solid-phase peptide synthesis, but during the synthesis, several impurities such as aggregated peptides are generated. Therefore, the purity of Icatibant is increased by removing these impurities from the crude Icatibant obtained by the synthesis reaction. For example, Patent Document 1 proposes a method for separating and purifying Icatibant using reverse phase chromatography.

European Patent Application Publication No. 4083053

However, with the method of Patent Document 1, the recovery rate of icatibant is around 80-85%, resulting in a large amount of loss when applied to large-scale production. Because therapeutic drugs containing medium-sized molecular weight drugs such as icatibant are expensive, it is desirable to improve the recovery rate in order to reduce costs. On the other hand, if one attempts to further increase the recovery rate of medium-sized molecular weight drugs such as icatibant, the purity will decrease. This is because the crude product to be purified contains multiple types of impurities that have similar chemical properties to the medium-sized molecular weight drugs.

For these reasons, it is technically extremely difficult to increase the recovery rate by even 1% while maintaining high purity in the separation and purification of medium-molecule drugs such as icatibant.

The present invention aims to provide a separation and purification method and system that can purify high-purity medium-molecule pharmaceuticals with a high recovery rate, even when applied to large-scale production.

The inventors have conducted research into how to achieve high purity and high recovery rates in the purification of medium molecule pharmaceuticals, and have come up with a purification method using a two-stage process including primary and secondary treatment. In the primary treatment, the target product is recovered to the maximum extent by removing components that are easy to separate. In the secondary treatment, precision separation using a simulated moving bed is used. This purification method using a two-stage process including primary and secondary treatment can provide a separation and purification method and system that can achieve both high purity and high recovery rates even in large-scale production.

The present invention includes the following embodiments [1] to [14].
[1] A primary treatment step of supplying a treatment target liquid containing a medium molecular weight drug as a separation target and a plurality of impurities to a column packed with a separating agent X to obtain a primary treatment liquid from the treatment target liquid in which the following α component has been removed;
a secondary treatment step in which the primary treatment liquid is supplied to a plurality of packed sections filled with a separating agent Y to perform a simulated moving bed method for continuously separating the medium-molecule pharmaceuticals;
having
A method for separating and purifying a medium-sized molecule drug, wherein the medium-sized molecule drug is a peptide drug or a nucleic acid drug containing a compound having a molecular weight of 500 to 10,000;
The α component is the impurity, among the multiple impurities in the treatment target liquid, that has the smallest overlap with the peak area of the medium molecule drug in the chromatogram of the treatment target liquid obtained by the primary treatment step.
[2] The separation and purification method described in [1], wherein the medium-sized molecule drug is icatibant.
[3] The method further comprises the following α component selection step prior to the primary treatment step:
The α component selection step includes a step of determining a first peak corresponding to the medium molecule drug in a chromatogram obtained when the treatment target liquid is supplied to a column packed with the separating agent X;
determining a second peak corresponding to an impurity that has passed through the separating agent X before the medium molecule drug, among the plurality of impurities, in the chromatogram;
determining a third peak corresponding to an impurity that has passed through the separating agent X after the medium molecule drug;
selecting, as an α component, an impurity corresponding to a peak having a smallest overlapping area with the first peak among the second peak and the third peak;
The method for separation and purification according to [1] or [2],
[4] The separation and purification method according to any one of [1] to [3], wherein in the chromatogram of the primary treatment step, a fraction of the treatment target liquid from the starting point of a first peak corresponding to the medium molecule drug is retained to obtain a primary treatment liquid, and the impurities that flow out before obtaining the primary treatment liquid are removed.
[5] The separation and purification method according to any one of [1] to [4], wherein in the chromatogram of the primary treatment step, a fraction of the treatment target liquid corresponding to the peak formed by the medium molecular weight drug and the peak of an α component is retained to obtain a primary treatment liquid, and the α component that flows out after obtaining the primary treatment liquid is removed.
[6] The separation and purification method according to any one of [1] to [5], wherein the separating agent X is a synthetic adsorbent.
[7] The secondary treatment step comprises:
a supply/withdrawal step of supplying the primary treatment liquid and the eluent to at least two or more different filling sections among the plurality of filling sections, respectively, and withdrawing a separated liquid from each of the filling sections to which the primary treatment liquid and the eluent have been supplied, respectively;
a circulation step of circulating the primary treatment liquid and the eluent between the plurality of loading sections in the same flow direction as in the supply and withdrawal step without additionally supplying the primary treatment liquid and the eluent to the plurality of loading sections;
The method for separation and purification according to any one of [1] to [6],
[8] The separation and purification method according to any one of [1] to [7], wherein the separating agent Y is a synthetic adsorbent.
[9] The ^separation and purification method according to any one of [1] to [8], wherein in the secondary treatment step, the primary treatment liquid is supplied to at least one of the plurality of packed sections ^under a condition of a space velocity of 0.5 h −1 to 10 h −1 .
[10] The method for separation and purification according to any one of [1] to [9], wherein in the secondary treatment step, the pH of the eluent is adjusted to 7.0 or less.

[11] A primary treatment device for supplying a treatment target liquid containing a medium molecular weight drug as a separation target and a plurality of impurities to a column packed with a separating agent X to obtain a primary treatment liquid from the treatment target liquid in which at least a part of the following α component has been removed;
a simulated moving bed apparatus for performing a simulated moving bed method in which the primary treatment liquid is supplied to a plurality of packed sections filled with a separating agent Y, thereby continuously separating the medium-molecule pharmaceuticals;
Equipped with
a system for separating and purifying a medium-sized molecule drug, wherein the medium-sized molecule drug is a peptide drug or a nucleic acid drug containing a compound having a molecular weight of 500 to 10,000;
The α component is the impurity, among the plurality of impurities in the liquid to be treated, that has the smallest overlap with the peak area of the icatibant in the chromatogram of the liquid to be treated obtained by the primary treatment device.
[12] The separation and purification system according to [11], wherein the separating agent X is a synthetic adsorbent.
[13] The simulated moving bed apparatus has a supply section for separately supplying the primary treatment liquid and the eluent to each of the plurality of packed sections, and a withdrawal section for withdrawing the separated liquid from each of the plurality of packed sections;
The separation and purification system according to [11] or [12], wherein a circulation path satisfying the following conditions 1 and 2 is formed in the simulated moving bed apparatus:
Condition 1: The primary treatment liquid and the elution liquid are not additionally supplied to the plurality of loading sections.
Condition 2: The primary treatment liquid and the eluent circulate among the plurality of loading sections in a direction from the supply section toward the withdrawal section.
[14] The separation and purification system according to any one of [11] to [13], wherein the separating agent Y is a synthetic adsorbent.

　According to the present invention, even when applied to large-scale production, it is possible to purify high-purity medium-molecule pharmaceuticals with a high recovery rate.

FIG. 1 shows an enlarged view of a portion of an example of a chromatogram of a liquid to be treated obtained in a primary treatment. FIG. 2 shows an enlarged portion of an example of a chromatogram of the treatment target liquid obtained in the primary treatment. FIG. 3 shows an example of the configuration of the primary processing device. FIG. 4 shows an example of the configuration of the simulated moving bed apparatus. FIG. 5 shows an example of an operation flow of the simulated moving bed apparatus of FIG. FIG. 6 shows the concentration distribution of the P and R components in the packed section of the simulated moving bed apparatus of FIG. FIG. 7 shows the flow directions of the primary processing solution and the eluent in the loading section when steps 101 and 102 in FIG. 5 are repeated four times.

The meaning of the terms is as follows:
In this specification, a component that has a stronger interaction with the separating agent may be referred to as a P component. A component that has a weaker interaction with the separating agent may be referred to as an R component. When the liquid to be treated is passed through the separating agent, the R component passes through at a higher rate than the P component. Therefore, the R component tends to advance in the direction of liquid passage, and the P component tends to remain behind. As a result, the P component and the R component are separated. A liquid that is rich in either the P component or the R component after separation of the components may be referred to as a "separated liquid".

In this specification, α components and β components are not single impurity components, but a collective term for components that have weaker interactions with the separating agent than medium molecular weight drugs, and components that have stronger interactions with the separating agent than medium molecular weight drugs. The strength of the interaction between α components and β components varies depending on the separating agent, and also on the composition of the liquid being treated with the medium molecular weight drug.

In this specification, the use of "~" to indicate a range of values means that the values before and after it are included as the lower and upper limits.

[Medium molecule drugs]
Medium-sized molecule drugs are drugs that mainly contain compounds with a molecular weight of 500 to 10,000. Examples of medium-sized molecule drugs include peptide drugs and nucleic acid drugs.

Peptide drugs have a molecular weight of 500-6000 and mainly contain peptides with multiple amino acid residues. Peptide drugs are broadly divided into conventional peptide drugs that are composed of natural amino acids and next-generation peptide drugs that are composed of non-natural amino acids. Conventional peptide drugs generally have 8-50 amino acid residues and may have a molecular weight of 500-6000. Next-generation peptide drugs generally have 8-20 amino acid residues and may have a molecular weight of 500-3000.

Next-generation peptide drugs include, for example, glucagon-like peptide 1 (GLP-1 receptor agonists) such as dulaglutide, semaglutide, liraglutide, and tirzepatide, as well as leuprorelin, teriparatide, and icatibant.

Nucleic acid medicines are a general term for medicines whose basic structure is nucleotides, which are components of DNA and RNA that control the genetic information of living organisms, and their derivatives. Examples include antisense, siRNA (small interfering RNA), miRNA (microRNA), decoys, aptamers, and CpG oligos (CpG-ODN).

When separating and purifying medium-sized molecular weight drugs such as peptide drugs and nucleic acid drugs, the interaction between the impurities and the separation agent is similar to that between the target medium-sized molecular weight drug and the separation agent, making separation difficult. In the following embodiment, we will explain the purification of icatibant, a type of peptide drug, as the target medium-sized molecular weight drug.

[Summary of Icatibant separation and purification]
In the separation and purification of icatibant, impurities are separated and removed from a liquid to be treated that contains icatibant and a number of impurities. The liquid to be treated is a liquid to be separated in order to recover icatibant. As the liquid to be treated, crude icatibant obtained by a peptide solid-phase synthesis method is usually used, but is not particularly limited. The crude icatibant contains a number of impurities in addition to icatibant. For example, a synthetic product from Hamari Pharmaceutical Co., Ltd. can be used.

The inventors came up with the idea of incorporating the Simulated Moving Bed Chromatography (SMB) method of continuous liquid chromatography into the separation process in order to increase the recovery rate while maintaining the high purity of icatibant. As a result, they discovered that in order to increase the recovery rate, it is effective to remove the impurity that has the smallest overlap of peak areas with icatibant in the chromatogram among the multiple impurities in the liquid to be treated as a pretreatment for applying the SMB method.

Here, the impurity with the smallest overlap of the peak areas of icatibant is defined as the α component, and the selection process of the α component will be described in more detail. In an example of a chromatogram of the liquid to be treated shown in a partially enlarged view in Figure 1, peak C1 is the detection peak of icatibant. In Figure 1, impurity peaks C2 and C3 are shown, but in addition to the impurities corresponding to these two peaks, normal crude icatibant contains many impurities not shown.
In the chromatogram, the area of overlap S3 with the peak area of icatibant is the smallest, so the component corresponding to peak C3 is selected as the α component. On the other hand, the area of overlap S2 with the peak area of icatibant is larger than the area of overlap S3. Therefore, the component corresponding to peak C2 is not selected as the component to be removed in the pretreatment (primary treatment) step.

In the present invention, the simulated moving bed method in the secondary treatment process can separate components that are not alpha components (for example, the beta component corresponding to peak C2 in the example shown in Figure 1). In the primary treatment process, in order to maximize the recovery rate of icatibant, the overlapping portion of icatibant and the beta component is recovered as a purified liquid. In the secondary treatment process (SMB), impurities such as beta components can be removed, so the content of beta components in the primary treatment liquid may be high. In this way, by combining the primary and secondary treatment processes, it is possible to achieve both a high recovery rate and purity of icatibant.

In the present invention, the α component is removed in the primary treatment, which is liquid chromatography. Among the impurities in the liquid to be treated, the α component has the smallest overlap with the peak area of icatibant in the chromatogram obtained by the primary treatment step. Therefore, even if the α component is removed in the pretreatment, the amount of the target icatibant removed and the loss are relatively small.
The present inventors have discovered that by further performing a simulated moving bed process using icatibant obtained from the primary treatment liquid, it is possible to achieve a high recovery rate while maintaining the high purity of icatibant, and have completed the present invention.

In the case of liquid chromatography in the primary treatment, multiple components can be separated in sequence by utilizing the difference in the interaction between each component in the treatment liquid and the separating agent. For example, as shown in Figure 1, in the case of a treatment liquid containing two types of impurities, an α component corresponding to peak C3 and a β component corresponding to peak C2, the β component, which has a smaller interaction with the separating agent, has a shorter retention time and is separated first. The α component, which has a larger interaction with the separating agent, has a longer retention time and is separated last.

However, the liquid to be treated is not limited to containing two types of impurities, and may contain three or more types of impurities. In that case, the components that overlap the peak area of icatibant in the chromatogram of the liquid to be treated are removed in order.

Below, several embodiments are described in detail with appropriate reference to the drawings, but the embodiments of the present invention are not limited to the following description. The dimensional ratios in the drawings are set for the convenience of explaining the embodiments, and may differ from the actual dimensions.

[Method for isolating and purifying icatibant]
The method for separating and purifying icatibant according to one embodiment includes a primary treatment step and a secondary treatment step. The primary treatment step and the secondary treatment step will be described in order below.

(Primary treatment process)
In the primary treatment step, a liquid to be treated containing icatibant and a plurality of impurities is supplied to a column packed with separating agent X, thereby obtaining a primary treatment liquid from which the α component has been removed from the liquid to be treated.
As already mentioned, among the multiple impurities in the liquid to be treated, the α component is the impurity that has the smallest overlap with the peak area of icatibant in the chromatogram of the liquid to be treated obtained by the primary purification.
The conditions for removing the α-components from the liquid to be treated can be determined by those skilled in the art by varying various conditions such as the type and concentration of the eluent, gradient conditions, injection pressure, flow rate, and temperature.

When using the primary treatment device 1 shown in Figure 3, the liquid to be treated containing icatibant and multiple impurities is supplied from a pipe 51 to a column 52 packed with a separating agent X. The alpha component is removed from the liquid to be treated by adjusting the interaction with the separating agent X in the column 52. An eluent is used to adjust the interaction with the separating agent X. The primary treatment liquid from which the alpha component has been removed is then recovered and obtained from a pipe 53.

In the chromatogram of the primary treatment step shown in Figure 2, the fraction of the liquid to be treated from the starting point of the icatibant peak C1 is retained to obtain the primary treatment liquid, and the β components that flow out before that can be removed.
In addition, by retaining the fraction of the liquid to be treated corresponding to the peak bottom formed by peak C1 of icatibant and peak C3 of the α component (shown in Figure 2), it is possible to obtain it as a primary treatment liquid, and then remove the α component that flows out thereafter.
As described above, it is preferable to obtain the fraction of the liquid to be treated from the start of icatibant peak C1 to the bottom of the peak formed by icatibant peak C1 and α component peak C3 as the primary treatment liquid (gray range in Figure 2).

The content of the α component in the primary treatment liquid obtained in the primary treatment step is preferably as close to 0 as possible from the viewpoint of the purity of the icatibant in the secondary treatment. For example, the content is preferably 1.0% by mass or less, more preferably 0.5% by mass or less, and even more preferably 0.1% by mass or less.
The content of the α component is obtained as follows.
(Content of α component) = (mass of α component) / ((mass of total impurities) + (mass of Icatibant))

The purity of icatibant in the primary treatment liquid obtained in the primary treatment step is preferably 90% by mass or more, more preferably 94% by mass or more, and even more preferably 97% by mass or more, since this tends to increase the recovery rate of icatibant.
The purity of icatibant is obtained as follows.
(Purity of Icatibant) = (Mass of Icatibant) / ((Mass of total impurities) + (Mass of Icatibant))

(Separating agent X in the primary treatment process)
As the separating agent X, various separating agents used in the field of liquid chromatography can be used without any restrictions. For example, polymer-based separating agents made of polymer materials and inorganic-based separating agents made of inorganic materials can be mentioned.

Examples of polymeric materials for polymer-based separating agents include vinyl-based synthetic polymers, diene-based synthetic polymers, condensation-based synthetic polymers, and curable synthetic polymers.

Examples of vinyl synthetic polymers include styrene synthetic polymers such as polystyrene (PS), (meth)acrylic synthetic polymers such as polymethyl methacrylate (PMMA), acetal synthetic polymers such as polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polyethylene (PE), polypropylene (PP), polyacrylonitrile (PAN), polyvinyl alcohol (PVA), and polyvinyl butyral, polyvinyl acetate (PVAc), polyacrylamide (PAA), and polyvinyl ether synthetic polymers.

Examples of diene-based synthetic polymers include polybutadiene (PBd) and polyisoprene (PIP).

Examples of condensation synthetic polymers include polyamide synthetic polymers such as nylon 6 and nylon 66, polyester synthetic polymers such as polyethylene terephthalate (PET) and polylactone, and polyether synthetic polymers such as polycarbonate (PC) and polyoxymethylene (POM).

Examples of curable synthetic polymers include polyurethane resins, alkyd resins, phenolic resins, polyaniline (PANI), epoxy-based synthetic polymers, and silicone-based synthetic polymers.

Other polymeric materials include xylene-based synthetic polymers, furan-based synthetic polymers, terpene-based synthetic polymers, petroleum-based synthetic polymers, ketone-based synthetic polymers, and sulfur-based synthetic polymers such as polycyclic thioethers.

Examples of inorganic materials for inorganic separating agents include activated carbon, silica gel, diatomaceous earth, hydroxyapatite, alumina, titanium oxide, magnesia, and polysiloxane.

Among them, polymer-based separating agents are preferred as separating agent X in terms of separation ability, and synthetic adsorbents are more preferred. Synthetic adsorbents are polymers that have a porous structure and a cross-linked structure. Synthetic adsorbents can remove organic matter from the liquid to be treated by adsorption, utilizing the hydrophobic interactions caused by their hydrophobic sites.

The shape of the synthetic adsorbent is not particularly limited, but it can take various shapes such as spheres, ellipsoids, cylinders, and prisms. Among these, spherical synthetic adsorbents are preferred.

The average particle size of the synthetic adsorbent is not particularly limited, but may be in the range of, for example, 5 to 100 μm, 8 to 50 μm, 10 to 30 μm, etc. The average particle size of the synthetic adsorbent can be measured by known methods. For example, it can be obtained by measuring the particle sizes of 100 or more particles using an optical microscope and calculating the volume median diameter from the distribution.

Among the synthetic adsorbents used as the separating agent X, styrene-divinylbenzene synthetic adsorbents, Br-modified styrene-di-vinylbenzene synthetic adsorbents, and (meth)acrylic synthetic adsorbents are preferred, with styrene-divinylbenzene synthetic adsorbents being more preferred.

(Eluent in the primary treatment process)
The eluent used in the primary treatment is not particularly limited, and may be appropriately selected depending on the state of the liquid to be treated and the treatment conditions.
For example, the organic solvent may be acetonitrile, ethanol, or methanol, with acetonitrile being more preferred.
As the buffer for adjusting the pH, phosphates, acetates and ammonium salts are preferred, and phosphates are more preferred.

(Secondary treatment process)
In the secondary treatment step, a simulated moving bed method is performed in which the primary treatment liquid is supplied to a plurality of packed sections filled with separating agent Y to continuously separate the icatibant. Hereinafter, an example of carrying out the secondary treatment step using the simulated moving bed apparatus 2 shown in Fig. 4 will be described, but the secondary treatment step is not limited to this example.

(Separating agent Y in the secondary treatment process)
The separating agent used as separating agent Y may be selected from the same separating agents used in the primary treatment. Among them, synthetic adsorbents are preferred. As the type of synthetic adsorbent, styrene-divinylbenzene synthetic adsorbents, Br-modified styrene-di-vinylbenzene synthetic adsorbents, and (meth)acrylic synthetic adsorbents are preferred, and styrene-divinylbenzene synthetic adsorbents are more preferred.

The average particle size of the separating agent Y is not particularly limited, but may be, for example, in the range of 5 to 100 μm, 10 to 50 μm, 10 to 30 μm, etc. The average particle size of the synthetic adsorbent can be measured by a known method. For example, it can be obtained by measuring the particle sizes of 100 or more particles with an optical microscope and calculating the volume median diameter from the distribution.
The type and average particle size of the separating agent Y may be the same as those of the separating agent X, or may be selected independently.

(Eluent in the secondary treatment process)
The eluent used in the primary treatment may be selected similarly to the eluent used in the primary treatment, or may be selected independently. The buffer may be selected similarly to the eluent used in the primary treatment, or may be selected independently.

5 is a flow chart showing an example of the operation of the secondary treatment step of the simulated moving bed apparatus 2. As shown in FIG. 5, the simulated moving bed process in the secondary treatment step has a feed withdrawal step and a circulation step.
In the supply and withdrawal step, the primary treatment liquid and the eluent are supplied to at least two or more different packing sections among the multiple packing sections (11, 12, 13, 14), respectively, and the separated liquid is withdrawn from each packing section to which the primary treatment liquid and the eluent have been supplied, respectively.
In the circulation step, the primary treatment liquid and the eluent are not additionally supplied to the multiple packing sections (11, 12, 13, 14), but are circulated between the multiple packing sections (11, 12, 13, 14) in the same flow direction as in the supply/withdrawal step.

Figures 6(a) and 6(b) show the concentration distribution of the P and R components in the filling sections 11-14 during the supply/withdrawal step and the circulation step. Here, the horizontal direction represents the position within the filling sections 11-14. In Figure 6, the left side represents the upper (more upstream) position within the filling sections 11-14. Additionally, the right side represents the lower (more downstream) position within the filling sections 11-14.

6, the vertical direction represents the concentrations of the P component and the R component at each position. The right arrow represents the flow direction of the primary treatment liquid and the eluent in the packing sections 11-14. In this case, the right arrow means that the primary treatment liquid and the eluent flow downward in the packing sections 11-14. If the right arrow and the left arrow are not shown, it means that no flow occurs in the packing sections 11-14.
6, the down arrow and the up arrow indicate the points where the primary treatment liquid and the eluent are supplied, and the points where the P fraction, which is a separation liquid rich in the P component, and the R fraction, which is a separation liquid rich in the R component, are extracted. In the figure, the primary treatment liquid is represented by "F", the eluent by "W", the P component and the P fraction by "P", and the R component and the R fraction by "R".

In FIG. 6, the packing section 13 is labeled as the adsorption zone (Zone 1), the packing section 14 as the purification zone (Zone 2), the packing section 11 as the desorption zone (Zone 3), and the packing section 12 as the concentration zone (Zone 4). Separation operation can be performed continuously by shifting these zones one by one.

When the primary treatment liquid is passed through the separating agent Y in the filling sections 11-14, as described above, the passing speed of the R component is greater than the passing speed of the P component. Therefore, for example, as shown in Figure 6(a), the R component tends to move ahead in the direction of liquid passage, and the P component tends to remain behind. In other words, the P component and the R component are separated in the filling sections 11-14. Here, if the α component (corresponding to peak C3 in Figure 1) is a component that has a stronger retention than icatibant in the primary treatment process, the P component (corresponding to peak C1 in Figure 1) will be rich in icatibant.

In the state shown in FIG. 6(a), the primary treatment liquid and the eluent are supplied in a downward flow from separate supply parts. At the same time, the P-component-rich separated liquid and the R-component-rich separated liquid are each extracted from separate extraction parts (step 101: supply and extraction step). In this case, the primary treatment liquid on-off valve F3, the eluent on-off valve W1, the connection line on-off valves X1 and X2, the P-component on-off valve P1, and the R-component on-off valve R3 are opened, and the other on-off valves are closed. In this state, the primary treatment liquid can be supplied from the supply part 23 to the filling part 13, and the eluent can be supplied from the supply part 21 to the filling part 11. In addition, the P fraction, which is the P-component-rich separated liquid, can be extracted from the extraction part 31, and the R fraction, which is the R-component-rich separated liquid, can be extracted from the extraction part 33.

In the supply and extraction step of this example, the P component is eluted by the eluent supplied from the supply section 21 to the packing section 11. A part of the supplied eluent is extracted into the pipe HP1 as the P fraction, which is a separation liquid rich in the P component. The remaining part of the eluent that is not extracted from the extraction section 31 flows into the packing section 12 from the pipe HX1. As a result, the eluent moves downward and flows through the packing section 12 and the packing section 13. Then, as the separation of the P component and the R component progresses in the packing section 12 and the packing section 13, the concentration distribution of the P component and the R component also moves downstream. Then, the primary treatment liquid is supplied to the packing section 13, and the R fraction, which is a separation liquid rich in the R component, is extracted into the pipe HR3 from the extraction section 33 of the packing section 13.
Here, the amount of liquid extracted into the pipe HP1 is a portion of the amount of liquid supplied from the supply unit 21. Therefore, in order to control this flow rate, it is useful to attach a pump to the end of the pipe HP1 to extract a constant flow rate and to adjust the amount extracted with an integrating flow meter.

In the supply and withdrawal step exemplified here, the following operations may be separately carried out.
An operation of supplying a primary treatment liquid from the supply unit 23 and extracting an R fraction from the extraction unit 33. An operation of supplying an eluent from the supply unit 21 and extracting a P fraction from the extraction unit 31. An operation of supplying an eluent from the supply unit 21 and extracting an R fraction from the extraction unit 33.

At the end of step 101, the concentration distribution of the P and R components will be as shown in Figure 6(b). In the state shown in Figure 6(b), the primary treatment liquid and eluent in the filling section 10 are circulated between the filling sections 10 in a downward flow to advance the separation of the multiple components (step 102: circulation process).

In step 102, the primary treatment liquid and the eluent are not supplied. The connection line on-off valves X1, X2, and X3 are opened, and the other on-off valves are closed. The pump PM is then operated to circulate the primary treatment liquid and the eluent in the loading section 10 between the loading sections 10 in a downward flow. In this case, by opening the connection line on-off valves X1, X2, and X3, all the loading sections 10 are connected by the pipes HX1, HX2, HX3, and HX4 and the bypass line HB. As a result, a circulation path that satisfies the following conditions 1 and 2 is formed in the simulated moving bed apparatus 2.
Condition 1: The primary treatment liquid and the eluent are not additionally supplied to the multiple loading sections 10 .
Condition 2: The primary treatment liquid and the eluent are circulated among the multiple loading sections in a direction from the supply section 20 toward the withdrawal section 30.

By operating the pump PM, the primary treatment liquid and eluent can be moved within the circulation path. By executing the circulation step once, the primary treatment liquid and eluent within the filling section 10 can be moved downward by the width of one filling section 10. At this time, separation of the P component and the R component progresses. As a result, the concentration distribution is shifted by one filling section 10 to the right in FIG. 6 from the state shown in FIG. 6(a). In other words, the concentration distribution is reproduced by shifting one filling section 10 to the right in FIG. 6. This allows the process to return to step 101 again and repeat the same separation process, allowing separation by liquid chromatography to be performed continuously.

Next, as shown in Fig. 5, it is determined whether or not to terminate the separation by the simulated moving bed method (step 103). Separation may be terminated, for example, when a predetermined amount of the primary treatment liquid has been treated. Separation may also be terminated when the pressure loss exceeds a predetermined magnitude, or when a predetermined separation operation time has elapsed.
If separation is to be ended (Yes in step 103), the separation operation is stopped (step 104). On the other hand, if separation is not to be ended (No in step 103), the process returns to step 101. Thereafter, steps 101, 102 and 103 are repeated.

7(a) to 7(h) are diagrams showing the flow directions of the primary processing liquid and the eluent in the filling sections 11 to 14 when steps 101, 102, and 103 in FIG. 5 are repeated four times (step 1 to step 4). Here, Figs. 7(a) and 7(b) show one step, Figs. 7(c) and 7(d) show two steps, Figs. 7(e) and 7(f) show three steps, and Figs. 7(g) and 7(h) show four steps.
In Fig. 7, as in Fig. 6, a right arrow indicates a downward flow. Furthermore, if a right arrow is not shown, it means that no flow occurs in the packing sections 11 to 14. Downward arrows and upward arrows indicate the points where the primary treatment liquid and eluent are supplied and the points where the P fraction and R fraction are extracted. In this case, the primary treatment liquid is represented by "F", the eluent by "W", the P component and P fraction by "P", and the R component and R fraction by "R".

The following Table 1 shows the open state of each on-off valve of the switching unit 40 in each process shown in FIG. 7. All on-off valves other than those shown here are closed.

Comparing Figures 7(a) and 7(b), 7(c) and 7(d), 7(e) and 7(f), 7(g) and 7(h), the position of the flow direction, the points where the primary treatment liquid and eluent are supplied, and the points where the P fraction and R fraction are extracted are shifted by one valve to the right (downstream) in the figures for each filling section 10. Also, referring to Table 1, the positions of the on-off valves to be opened are similarly shifted by one valve to the right (downstream) in the figures for each filling section 10. After steps 1 to 4 are performed, the state returns to that of step 1. In other words, after Figure 7(h), the state returns to that of Figure 7(a).

In the secondary treatment step, it is preferable to supply the primary treatment liquid to at least one of the multiple packed sections (11, 12, 13, 14) under the condition of a spatial velocity (SV) of 0.5 h ^-1 to 10 ^h -1. The closer the spatial velocity is to the lower limit of the above-mentioned numerical range, the easier it is to improve the purity and recovery rate of Icatibant. The closer the spatial velocity is to the upper limit of the above-mentioned numerical range, the higher the productivity. It is preferable that the spatial velocity is a flow rate at which a pressure of about 0.8 times the column pressure resistance is applied.

In the secondary treatment process, the pH of the eluent in the multiple filling sections (11, 12, 13, 14) is preferably 7.0 or less, more preferably 5.0 or less, and even more preferably 3.0 or less.

(Mechanism of action)
The above-described method for separating and purifying icatibant removes α-components from the liquid to be treated by the primary treatment step. The α-components are impurities that have the smallest overlap with the peak area of icatibant in the chromatogram of the liquid to be treated. Therefore, the loss of icatibant is reduced and the recovery rate is improved. Then, based on the characteristics of icatibant and the α-component, the separating agent X, the eluent, the separation conditions, etc. are determined. In addition, according to the method for separating and purifying icatibant, in the secondary treatment step, icatibant can be continuously separated from the primary treatment liquid obtained in the primary treatment step. Therefore, the recovery rate is improved while maintaining the high purity of icatibant.

(α component selection process)
In one example, the purification method for icatibant may further include the following alpha component selection step before the primary treatment step:
The alpha component selection process includes the following steps.
A step of determining a first peak (C1) corresponding to icatibant in a chromatogram obtained when the liquid to be treated is supplied to a column packed with separating agent X.
A step of determining a second peak (C2) in the chromatogram, which corresponds to an impurity that has passed through the separating agent X before icatibant, among the plurality of impurities.
Determining the third peak (C3), which corresponds to the impurities that passed through the separating agent X after Icatibant.
a step of selecting, as the α component, an impurity corresponding to the peak having the smallest overlapping area with the first peak (C1) from among the second peak (C2) and the third peak (C3).

[Post-processing]
After the secondary treatment, a post-treatment may be carried out as necessary, such as a solvent removal treatment, a cation exchange treatment, or an anion exchange treatment.

[Icatibant separation and purification system]
The separation and purification system for Icatibant according to one embodiment includes a primary treatment device and a simulated moving bed device. The primary treatment device and the simulated moving bed device will be described below in order.

(Primary Processing Device)
The primary treatment device supplies a liquid to be treated, which contains icatibant and a plurality of impurities, to a column packed with separating agent X, thereby obtaining a primary treatment liquid from which the alpha component has been removed from the liquid to be treated.

For example, the primary treatment device 1 shown in FIG. 3 has a pipe 51, a column 52, and a pipe 53. According to the primary treatment device 1, the liquid to be treated containing icatibant and multiple impurities can be supplied from the pipe 51 to a column 52 filled with a separating agent X. In the column 52, the α component is removed from the liquid to be treated by adjusting the interaction with the separating agent X, that is, the impurity that has the smallest overlap with the peak area of icatibant in the chromatogram of the liquid to be treated.

The eluent used in the column 52 is used to adjust the interaction with the separating agent X, thereby removing the α component from the liquid to be treated. The eluent used in the primary treatment can be appropriately selected depending on the state of the liquid to be treated and the treatment conditions. Examples of the eluent include acetonitrile, ethanol, and methanol. Among these, acetonitrile is more preferable.
The primary treated liquid from which the α component has been removed can be recovered and obtained from the pipe 53 .

The alpha component content of the primary treatment liquid obtained in the primary treatment device is preferably as close to 0 as possible from the viewpoint of the purity of the ikativant in the secondary treatment. For example, 1.0% by mass or less is preferable, 0.5% by mass or less is more preferable, and 0.1% by mass or less is even more preferable.

The content of icatibant in the primary treatment liquid obtained by the primary treatment device is preferably 90% by mass or more, more preferably 94% by mass or more, and even more preferably 97% by mass or more, since the recovery rate of icatibant by secondary treatment is likely to be high. Since impurities other than the alpha component can be removed by secondary treatment, it may be included in the primary treatment liquid.

Details and preferred aspects of the separating agent X are the same as those described for the separation and purification method, and a synthetic adsorbent is preferred. Details and preferred aspects of the synthetic adsorbent are also the same as those described for the separation and purification system.

(Simulated moving bed device)
The simulated moving bed apparatus performs a simulated moving bed method for continuously separating icatibant by supplying the primary treated liquid obtained in the primary treatment apparatus to a plurality of packed sections filled with separating agent Y. The simulated moving bed apparatus is not particularly limited as long as it is an apparatus for performing the simulated moving bed method using the primary treated liquid obtained in the primary treatment apparatus as the liquid to be separated.

For example, the simulated moving bed apparatus 2 shown in Figure 4 can perform a simulated moving bed method for continuously separating icatibant by supplying the primary treatment liquid to multiple packed sections 10 (11, 12, 13, 14) filled with separating agent Y.
The simulated moving bed apparatus 2 has a filling section 10, a supply section 20, a withdrawal section 30 and a switching section 40.

The filling section 10 is a section for separating the icatibant from impurities.
Four packing sections 10 are provided in one simulated moving bed apparatus 2. In the example shown in Fig. 4, packing sections 11, 12, 13, and 14 (packing sections 11 to 14) are illustrated as the packing sections 10. Hereinafter, when there is no need to distinguish between the packing sections 11, 12, 13, and 14, they may be simply referred to as packing section 10. When the separation conditions need to be adjusted based on the state of the primary treatment liquid, etc., five or more packing sections 10 may be provided in one simulated moving bed apparatus 2.

The filling section 10 is filled with a separating agent Y for separating icatibant contained in the primary treatment liquid. Examples of separating agent Y include the same separating agents as those exemplified for separating agent X in the primary treatment device, and a synthetic adsorbent is preferred. In the entire icatibant separation and purification system, separating agent Y may be the same as separating agent X or may be different.

The separation tower packed with separating agent Y is preferably a packed column that does not have an empty column at the top. The packed section 10 may be, for example, a column. The packed section 10 has a space inside for packing with separating agent Y. Examples of materials for the packed section 10 include steel plate and resin. The liquid-contacting part may be lined with rubber, but this is not particularly limited. The shape of the packed section 10 is not particularly limited, but an example is a column with a roughly cylindrical shape.

The supply section 20 is a section for separately supplying the primary treatment liquid and the eluent to each of the multiple filling sections. The eluent is a liquid used for recovering the separation liquid rich in icatibant. The eluent is used to develop the components adsorbed in each filling section. The strength of the interaction between the separating agent Y and the adsorbed components can be adjusted by the eluent. By adjusting the interaction between the separating agent Y and the components by the concentration of the eluent, etc., each component can be separated and eluted.

The eluent used in the secondary treatment can be appropriately selected depending on the state of the primary treatment liquid and the treatment conditions. Examples include acetonitrile, methanol, and ethanol. Of these, acetonitrile is preferred. The eluent used in the secondary treatment may be the same as the eluent used in the primary treatment, or it may be different. From the viewpoint of ease of management, it is preferable that the eluent used in the secondary treatment is the same as the eluent used in the primary treatment.

In the example shown in FIG. 4, the supply unit 20 is formed as a supply port at the top of each filling unit. To explain in more detail, supply units 21, 22, 23, and 24 (supply units 21 to 24) are shown as the supply unit 20. Hereinafter, when there is no need to distinguish between each of the supply units 21, 22, 23, and 24, they may be simply referred to as supply unit 20.

The extraction section 30 is a section for extracting the separated liquid from each of the multiple filling sections. In the example shown in FIG. 4, the extraction section 30 is formed as a discharge outlet at the bottom of each filling section. To explain in more detail, the extraction section 30 is illustrated as extraction sections 31, 32, 33, and 34 (extraction sections 31 to 34). Hereinafter, when there is no need to distinguish between each of the extraction sections 31, 32, 33, and 34, they may be simply referred to as extraction section 30.

The switching unit 40 is a part for switching the flow paths. In the example shown in FIG. 4, the switching unit 40 includes a plurality of on-off valves. By opening and closing the plurality of on-off valves, the flow paths of the primary treatment liquid, eluent, and separation liquid can be switched. In more detail, the switching unit 40 includes eluent on-off valves W1, W2, W3, and W4, primary treatment liquid on-off valves F1, F2, F3, and F4, connection path on-off valves X1, X2, X3, and X4, R component on-off valves R1, R2, R3, and R4, and P component on-off valves P1, P2, P3, and P4.

The simulated moving bed apparatus 2 has a pipe HW for supplying the eluent, a pipe HW1 for supplying the eluent from the pipe HW to the filling section 11, a pipe HW2 for supplying the eluent from the pipe HW to the filling section 12, a pipe HW3 for supplying the eluent from the pipe HW to the filling section 13, and a pipe HW4 for supplying the eluent from the pipe HW to the filling section 14. The eluent on-off valves W1 to W4 are provided in the pipes HW1 to HW4, respectively, and control the supply of the eluent to the filling sections 11 to 14.

The simulated moving bed apparatus 2 has a pipe HF for supplying the primary treatment liquid, a pipe HF1 for supplying the primary treatment liquid from the pipe HF to the filling section 11, a pipe HF2 for supplying the primary treatment liquid from the pipe HF to the filling section 12, a pipe HF3 for supplying the primary treatment liquid from the pipe HF to the filling section 13, and a pipe HF4 for supplying the primary treatment liquid from the pipe HF to the filling section 14. Primary treatment liquid on-off valves F1 to F4 are provided in the pipes HF1 to HF4, respectively, and control the supply of the primary treatment liquid to the filling sections 11 to 14.

The simulated moving bed device 2 has, as connection paths connecting each filling section 10, a pipe HX1 connecting the discharge section 31 of the filling section 11 to the supply section 22 of the filling section 12, a pipe HX2 connecting the discharge section 32 of the filling section 12 to the supply section 23 of the filling section 13, a pipe HX3 connecting the discharge section 33 of the filling section 13 to the supply section 24 of the filling section 14, and a pipe HX4 connecting the discharge section 34 of the filling section 14 to the supply section 21 of the filling section 11. The connection path opening/closing valves X1 to X4 are provided in the pipes HX1 to HX4, respectively, and control the flow of liquid between the filling sections 11 to 14.

A bypass path HB is provided at the connection path on-off valve X4 of pipe HX4. A pump PM is provided in the bypass path HB. Although the bypass path HB and the pump PM are installed in pipe HX4, they may be installed in any of pipes HX1 to HX4, or in multiple positions (for example, all positions) of pipes HX1 to HX4.

The simulated moving bed apparatus 2 has a pipe HR for extracting the R fraction, a pipe HR1 for extracting the R fraction from the filling section 11 to the pipe HR, a pipe HR2 for extracting the R fraction from the filling section 12 to the pipe HR, a pipe HR3 for extracting the R fraction from the filling section 13 to the pipe HR, and a pipe HR4 for extracting the R fraction from the filling section 14 to the pipe HR. The R component on-off valves R1 to R4 are provided in the pipes HR1 to HR4, respectively, and control the extraction of the separated liquid from the filling sections 11 to 14.

The simulated moving bed apparatus 2 has a pipe HP for extracting the P fraction, a pipe HP1 for extracting the P fraction from the packing section 11 to the pipe HP, a pipe HP2 for extracting the P fraction from the packing section 12 to the pipe HP, a pipe HP3 for extracting the P fraction from the packing section 13 to the pipe HP, and a pipe HP4 for extracting the P fraction from the packing section 14 to the pipe HP. P component on-off valves P1 to P4 are provided in the pipes HP1 to HP4, respectively, and control the extraction of the separated liquid from the packing sections 11 to 14.

In order to maintain a constant solubility of the solute, it is preferable to maintain a constant temperature inside the simulated moving bed apparatus 2. To maintain a constant temperature, the piping and columns may be covered with thermal insulation material, or a heat exchanger may be installed in places where the temperature is likely to fluctuate. Ultrasound may also be applied to promote dissolution of the solute components.

(Mechanism of action)
The above-described Icatibant separation and purification system removes α-components from the liquid to be treated by the primary treatment device. The α-components are impurities that have the smallest overlap with the peak area of Icatibant in the chromatogram of the liquid to be treated. Therefore, the loss of Icatibant is reduced and the recovery rate is improved. Then, based on the characteristics of Icatibant and the α-component, the separating agent X, the eluent, the separation conditions, etc. are determined. In addition, according to the Icatibant separation and purification system, Icatibant can be continuously separated from the primary treatment liquid obtained by the primary treatment device by the simulated moving bed device. Therefore, the recovery rate is improved while maintaining the high purity of Icatibant.

The above describes the embodiments of the present invention based on specific examples, but each embodiment is presented as an example and does not limit the scope of the present invention. Each embodiment described in this specification can be modified in various ways without departing from the spirit of the invention, and can be combined with features described in other embodiments to the extent that they are feasible.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following description.

[Example 1]
(α component selection process)
Crude icatibant synthesized by Hamari Chemical Industry Co., Ltd. was obtained and prepared. The synthetic adsorbent, eluent, and crude icatibant were subjected to liquid chromatography under the following conditions.
Purification equipment: SHOKO SCIENTFIC product "Medium-high pressure separation purification equipment Purif-Rp2"
Separating agent X: styrene divinylbenzene (Mitsubishi Chemical Corporation product "MCIGEL CHP20/P10", average particle size 10 μm)
Column size: 20φ×15mmh (47mL)
Eluent A: acetonitrile/50 mM Na ₃ PO ₄ (pH 2.0, H ₃ PO ₄ )=5/95
Eluent B: acetonitrile/50 mM _{Na3PO4 (} pH 2.0, _H3PO4 )/ _{H2O =} 8/1/1
Flow rate: 18ml/min
Raw material: Crude icatibant 100 mg/mL
Injection volume: 9 mL
Temperature: 25°C
Detection: UV (220 nm, Prep cell)

The gradient slopes (one cycle) of eluent A and eluent B are shown in Table 2 below.

The chromatogram obtained is shown in an enlarged view in Figure 1. The component corresponding to peak C3, which has the smallest area overlap with the icatibant peak, was selected as the α component.

(Primary Processing)
Primary treatment was carried out under the same conditions as those for the selection of the α component described above, and the fraction between 12.00 minutes and 14.25 minutes in the cycle shown in Table 2 was collected as the icatibant primary treatment liquid.

After primary treatment, the purity of icatibant was 97.0% by mass, the alpha component content was 0.7% by mass, and the recovery rate of icatibant was 98.0%.

(Secondary treatment)
A separation test of the primary treatment liquid obtained in the primary treatment was carried out by using the simulated moving bed apparatus 2 shown in Figure 4. The secondary treatment conditions were as follows.
Purification equipment: Mitsubishi Chemical Aqua Solutions' product "LaboFine"
Separating agent Y: styrene-divinylbenzene (Mitsubishi Chemical Corporation product "MCIGEL CHP20/P20", average particle size 20 μm)
Column size: 4.6φ×250mmh×4 (16.6mL)
Eluent: acetonitrile/50 mM Na ₃ PO ₄ (pH 2.0, H ₃ PO ₄ )=20/80
Flow rate: 0.8 ml/mL (space velocity (SV): 2.9 h ^-1 )
Raw material: Refined liquid obtained in the primary treatment process Temperature: 25°C

Table 3 shows the liquid volume for each step in any one of steps 1 to 4 shown in Figure 7. In addition, run 1 shown in Table 3 is a condition that prioritizes icatibant purity, and run 2 is a condition that prioritizes icatibant recovery rate.

In Run 1, in which the purity of icatibant was prioritized, the purity of icatibant was 99.3% and the recovery rate was 95.5% or more.
In Run 2, in which the recovery rate of icatibant was prioritized, the purity of icatibant was 99.2% and the recovery rate was 97.5% or more.

The total recovery rate of icatibant in the primary and secondary treatments was 93.6% in run 1 and 95.5% in run 2. The total recovery rate was obtained by the following formula:
(Total recovery rate) = (Icatibant recovery rate in primary treatment) x (Icatibant recovery rate in secondary treatment)

[Comparative Example 1]
Under the same primary treatment conditions as in Example 1, the fraction from 12.50 minutes to 14.25 minutes in the cycle shown in Table 2 was collected to separate the α component and the β component, and icatibant was purified by primary treatment alone.

As a result, when icatibant was purified using only the primary treatment, the purity of icatibant was 99.6% and the recovery rate was 82.0%.

[Comparative Example 2]
Icatibant was purified by isocratic elution (not the simulated moving bed method) using the primary treatment liquid obtained in Example 1. The separation conditions were the same as those in the secondary treatment step in Example 1, except for the raw material supply amount: 0.8 ml.

As a result, when fractionated to obtain icatibant with a purity of 99% or more, the purity of icatibant was 99.6%, with a recovery rate of 86.3%. The total recovery rate of icatibant, including the primary treatment, was 84.6%.

The results of Example 1 confirmed that by combining primary and secondary treatments, it is possible to purify highly pure icatibant with a high recovery rate, even when applied to large-scale production.

[Example 2]
The crude icatibant was purified under the same conditions as in Example 1, except that Sepabeads SP20SS (average particle size 70 μm) manufactured by Mitsubishi Chemical Corporation was used as separating agent Y in the secondary treatment. The results are shown in Table 4.

[Example 3]
The crude icatibant was purified under the same conditions as in Example 1, except that the space velocity (SV) of the secondary treatment was changed to 9.8 h ⁻¹ . The results are shown in Table 4.

[Comparative Example 3]
In Example 1, the crude icatibant was purified under the same conditions as in Example 1, except that the crude icatibant was used directly in the secondary treatment without carrying out the primary treatment. However, the impurities could not be peeled off from the separating agent, and the purification and separation were not possible.

　According to the present invention, even when applied to large-scale production, it is possible to purify high-purity medium-molecule pharmaceuticals with a high recovery rate.

1...Primary treatment device, 2...Simulated moving bed device, 10 (11, 12, 13, 14)...Filling section, 20 (21, 22, 23, 24)...Supply section, 30 (31, 32, 33, 34)...Extraction section, 40...Switching section.

Claims (14)

a primary treatment step of supplying a treatment target liquid containing a medium molecular weight drug as a separation target and a plurality of impurities to a column packed with a separating agent X to obtain a primary treatment liquid from the treatment target liquid in which the following α component has been removed;
a secondary treatment step in which the primary treatment liquid is supplied to a plurality of packed sections filled with a separating agent Y to perform a simulated moving bed method for continuously separating the medium-molecule pharmaceuticals;
having
A method for separating and purifying a medium-sized molecule drug, wherein the medium-sized molecule drug is a peptide drug or a nucleic acid drug containing a compound having a molecular weight of 500 to 10,000;
The α component is the impurity, among the multiple impurities in the treatment target liquid, that has the smallest overlap with the peak area of the medium molecule drug in the chromatogram of the treatment target liquid obtained by the primary treatment step. The separation and purification method according to claim 1, wherein the medium-sized molecule drug is icatibant. The method further includes the following α component selection step before the primary treatment step:
The α component selection step includes a step of determining a first peak corresponding to the medium molecule drug in a chromatogram obtained when the treatment target liquid is supplied to a column packed with the separating agent X;
determining a second peak corresponding to an impurity that has passed through the separating agent X before the medium molecule drug, among the plurality of impurities, in the chromatogram;
determining a third peak corresponding to an impurity that has passed through the separating agent X after the medium molecule drug;
selecting, as an α component, an impurity corresponding to a peak having a smallest overlapping area with the first peak among the second peak and the third peak;
The method for separation and purification according to claim 1 or 2, The separation and purification method according to claim 1 or 2, in which, in the chromatogram of the primary treatment step, a fraction of the treatment target liquid from the start point of a first peak corresponding to the medium molecule drug is reserved to obtain a primary treatment liquid, and the impurities that flow out before obtaining the primary treatment liquid are removed. The separation and purification method according to claim 1 or 2, in which a fraction of the liquid to be treated corresponding to the peak of the medium molecular weight drug and the peak of the α component is retained in the chromatogram of the primary treatment step to obtain a primary treatment liquid, and the α component that flows out after obtaining the primary treatment liquid is removed. The separation and purification method according to claim 1 or 2, wherein the separating agent X is a synthetic adsorbent. The secondary treatment step comprises:
a supply/withdrawal step of supplying the primary treatment liquid and the eluent to at least two or more different filling sections among the plurality of filling sections, respectively, and withdrawing a separated liquid from each of the filling sections to which the primary treatment liquid and the eluent have been supplied, respectively;
a circulation step of circulating the primary treatment liquid and the eluent between the plurality of loading sections in the same flow direction as in the supply and withdrawal step without additionally supplying the primary treatment liquid and the eluent to the plurality of loading sections;
The method for separation and purification according to claim 1 or 2, The separation and purification method according to claim 1 or 2, wherein the separating agent Y is a synthetic adsorbent. 3. The separation and purification method according to claim 1, wherein in the secondary treatment step, the primary treatment liquid is supplied to at least one of the plurality of packed sections at a space velocity of 0.5 h ⁻¹ to 10 h ⁻¹ . The separation and purification method according to claim 1 or 2, wherein the pH of the eluent is set to 7.0 or less in the secondary treatment step. a primary treatment device that supplies a treatment target liquid containing a medium molecular weight drug as a separation target and a plurality of impurities to a column packed with a separating agent X to obtain a primary treatment liquid from the treatment target liquid in which at least a part of the following α component has been removed;
a simulated moving bed apparatus for performing a simulated moving bed method in which the primary treatment liquid is supplied to a plurality of packing sections packed with a separating agent Y, thereby continuously separating the medium-molecule pharmaceuticals;
Equipped with
a system for separating and purifying a medium-sized molecule drug, wherein the medium-sized molecule drug is a peptide drug or a nucleic acid drug containing a compound having a molecular weight of 500 to 10,000;
The α component is the impurity, among the plurality of impurities in the liquid to be treated, that has the smallest overlap with the peak area of the icatibant in the chromatogram of the liquid to be treated obtained by the primary treatment device. The separation and purification system according to claim 11, wherein the separating agent X is a synthetic adsorbent. The simulated moving bed apparatus has a supply section for separately supplying the primary treatment liquid and the eluent to each of the plurality of packed sections, and a withdrawal section for withdrawing a separated liquid from each of the plurality of packed sections,
13. The separation and purification system according to claim 11 or 12, wherein a circulation path satisfying the following conditions 1 and 2 is formed in the simulated moving bed apparatus.
Condition 1: The primary treatment liquid and the elution liquid are not additionally supplied to the plurality of loading sections.
Condition 2: The primary treatment liquid and the eluent circulate among the plurality of loading sections in a direction from the supply section toward the withdrawal section. The separation and purification system according to claim 11 or 12, wherein the separating agent Y is a synthetic adsorbent.

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