CN113831283A - Preparation method of amorphous matter of Ranuncutinib salt - Google Patents
Preparation method of amorphous matter of Ranuncutinib salt Download PDFInfo
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- CN113831283A CN113831283A CN202111296789.6A CN202111296789A CN113831283A CN 113831283 A CN113831283 A CN 113831283A CN 202111296789 A CN202111296789 A CN 202111296789A CN 113831283 A CN113831283 A CN 113831283A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and particularly discloses a preparation method of a varenib mesylate amorphous substance, which adopts pure water as a solvent, dissolves a varenib mesylate C crystal form in purified water, and prepares the varenib mesylate amorphous substance through the procedures of stirring, cooling, freeze-drying and drying, the method does not use any organic solvent, is green and environment-friendly, saves the cost, has low energy consumption and simple operation, can freeze-dry and vacuum-dry within 24h to prepare high-purity varenib mesylate salt, avoids the risk of raising genotoxic impurities in the prior patent, does not produce impurities in the preparation process, and the prepared varenib mesylate has high purity, less water content and increased solubility and meets the medicinal standard; the medicinal composition prepared by using the amorphous substance has obvious dissolution advantage.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method of an amorphous substance of a Lunvatinib salt, in particular to a preparation method of an amorphous substance of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide mesylate.
Background
Lunvatinib mesylate (Lenvatinib Mesilate), chemical name: the 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide mesylate is an oral effective multi-kinase inhibitor developed by the Japan defense company, mainly acts on a plurality of targets such as c-Kit, Ret and VEGFR-2, and is used for treating solid tumors such as glioma, thyroid tumor, renal cancer, liver cancer, ovarian cancer and the like. Us FDA orphan drug was obtained 2 months 2013 and was clinically used for the treatment of follicular, medullary, undifferentiated metastatic or locally advanced papillary thyroid carcinoma.
Amorphous form is the form of drug that is most beneficial in enhancing drug efficacy in the metastable state. Amorphous is a particular crystalline state. In industrial production, a small amount of structural destruction of the compound surface may occur to become an amorphous state. The conventional instrument is difficult to detect a small amount of amorphous, the physical properties of the amorphous structure of the drug are greatly different from the crystal form structure, the amorphous structure can greatly influence the properties of the product such as stability, compatibility, dissolution rate, hygroscopicity and solvent adsorption tendency, and the existence of the amorphous structure can greatly influence the stability of the drug in the production and storage processes, thereby causing the failure of the whole new drug development. The phenomenon that the medicinal crystal form C is converted into an amorphous substance exists in a preparation process of the varlitinib mesylate, so that the crystal form C and the amorphous substance exist in a tablet of the varlitinib mesylate at the same time; in addition, the report shows that the methanesulfonic acid lunvatinib salt can not be gelatinized in an amorphous state, and can be quickly dissolved without adding an alkaline auxiliary material in the preparation process of the preparation. Therefore, the stable amorphous compound of the varlitinib mesylate is provided, is crucial to the research on qualitative and quantitative analysis of amorphous substances in a varlitinib mesylate tablet and the improvement of the safety and stability of a medicine, and can be used as a raw material medicine to improve the dissolution performance of a pharmaceutical preparation of the varlitinib mesylate.
The original patents CN101233111A, CN104755463A disclose amorphous crystals of varlitinib mesylate and a preparation method thereof, but the preparation method is not suitable for process scale-up. In the patent, an alcohol solvent is used for freeze-drying, the solubility of the alcohol to the salt of the Ranuncutinib is low, and meanwhile, a completely dissolved system is difficult to pre-freeze, needs extremely low temperature and has high requirements on equipment; and the alcohol solvent is easy to react with methanesulfonic acid in the methanesulfonic acid ranvatinib to generate genotoxic impurity mesylate, which is not beneficial to the safety and quality control of the medicament. Meanwhile, the method uses reduced pressure concentration distillation and heating reflux, and the method can cause the degradation of the methanesulfonic acid lunvatinib, so that the impurity content is high, and the method is not beneficial to the safety and quality control of the medicine.
Patent CN113087666A discloses a method for preparing amorphous pravastatin amorphous substance aiming at pravastatin C crystal form, alcohol/water mixed solvent such as tertiary butanol/water is used for dissolving, filtering is carried out, and filtrate is pre-frozen at-45 ℃ and freeze-dried at-45 to-10 ℃ to obtain the amorphous substance. The method avoids high temperature, and reduces the generation of degradation impurities; however, the method uses alcohols, which increases the risk of producing the genotoxic impurity mesylate. In addition, the amorphous Ranuncutinib compound prepared by the method disclosed by the patent still needs very low temperature (-45 to-10 ℃) although the freezing point of the mixed solvent of alcohol and water is higher than that of the alcohol, and the freeze-drying time is long, so that the preparation condition is high, the energy consumption is high, and the method is not green and environment-friendly.
Therefore, the research on the preparation process of the amorphous pravastatin sodium, which is green and environment-friendly, low in energy consumption and simple in operation, can stably prepare the high-purity amorphous pravastatin sodium compound, reduce the risk of generating genotoxic impurities in the preparation process, and stably provide the amorphous substance of pravastatin sodium for qualitative and quantitative analysis of the amorphous substance in the preparation and preparation of the preparation is of great significance.
Disclosure of Invention
The invention aims to provide a preparation method of a high-purity amorphous matter of a Ranuncutinib mesylate salt, which is green, environment-friendly, simple and convenient to operate and easy for industrial production, and particularly provides a preparation method of a Ranuncutinib mesylate amorphous matter, which is used for qualitative and quantitative analysis of the amorphous matter in a Ranuncutinib mesylate product or preparation of a preparation.
In order to achieve the aim, the invention discloses a preparation method of an amorphous matter of varenib mesylate, which comprises the following steps:
dissolving the crystalline form C of the pravastatin mesylate by using purified water at the temperature of 20-30 ℃, stirring and dissolving, cooling a pravastatin mesylate solution, setting the freeze-drying temperature and the freeze-drying time when the solution is completely solidified into a solid, and putting the solid into a freeze-dryer for freeze-drying to be powdery; and taking out the powdery solid, placing the powdery solid in a vacuum drying oven for vacuum drying, and performing vacuum drying for 10-12 hours under the conditions that the temperature of the vacuum drying oven is controlled to be 50-55 ℃ and the vacuum degree is less than-0.09 MPa to obtain the amorphous matter of the Ranuncutinib mesylate.
According to the embodiment of the invention, acetonitrile, ethanol, purified water and tert-butyl alcohol/water are respectively used as solvents to dissolve the pravastatin mesylate. Research shows that the pravastatin mesylate can be dissolved in purified water and a tert-butyl alcohol/water system at the temperature of 20-30 ℃, cannot be dissolved in ethanol and acetonitrile, and cannot be dissolved in acetonitrile with the volume of 400 times under the reflux condition. According to the invention, purified water is preferably used as a solvent for dissolving the varlitinib mesylate, and the dissolving temperature is selected from 20-30 ℃. The solvent may also be drinking water or distilled water.
According to the embodiment of the invention, the mass volume ratio of the pravastatin mesylate to the dissolved pravastatin mesylate is selected from 1:100 to 1:200, preferably 1: 110. The inventor researches and discovers that when the mass-volume ratio of the pravastatin mesylate to the purified water for dissolving the pravastatin mesylate is higher than 1:100, the pravastatin mesylate can not be completely dissolved, and a large amount of colloidal solid is generated; when the mass-volume ratio of the pravastatin mesylate to the purified water is 1: 100-1: 200, the pravastatin mesylate can be completely dissolved, the system is clear, and no obvious colloidal solid is generated.
According to the embodiment of the invention, when the amorphous matter of the pravastatin mesylate is prepared, the pravastatin mesylate can be completely solidified at-10-0 ℃ without obvious liquid or colloidal solid after being stirred and dissolved at 20-30 ℃ by adding purified water, and the preferable temperature is-5-0 ℃.
According to the embodiment of the invention, when the amorphous matter of the pravastatin mesylate is prepared, the freeze-drying can be carried out on the solid pravastatin mesylate water system at the temperature of below 0 ℃ by considering the freezing point of water, the freeze-drying temperature is preferably-5 ℃ to 0 ℃, and a vacuum pump is started to freeze-dry the solid pravastatin mesylate water system to be powder. Research shows that a small amount of ice cubes exist in a system with the freeze-drying time of less than 9 hours, a large amount of foamy solids appear, and the freeze-drying time is preferably 9-12 hours.
According to the embodiment of the inventionThe amorphous matter of the methanesulfonic acid lunvatinib prepared by the method disclosed by the invention is radiated by Cu-Kalpha, and has no sharp diffraction peak in an X-ray powder diffraction spectrum expressed by 2 theta; the infrared absorption spectrum measured by KBr pellet is 1050.384cm-1、1192.971cm-1、1454.558 cm-1、1647.389 cm-1、3304.492 cm-1Has an absorption peak.
Compared with the prior art, the invention provides a stable high-purity varlitinib mesylate amorphous substance which can be used for researching crystal forms of preparations, the preparation process of the high-purity varlitinib mesylate amorphous substance disclosed by the invention does not use any organic solvent, is green and environment-friendly, has low energy consumption and simple operation, can be used for preparing high-purity varlitinib mesylate salt by freeze-drying and vacuum drying within 24 hours, simultaneously avoids the risk of raising genotoxic impurities in the existing patent, does not produce impurities in the preparation process, and has high purity, low water content and increased solubility of the prepared varlitinib mesylate, thereby meeting the medicinal standard; the medicinal composition prepared by using the amorphous substance has obvious dissolution advantage.
Drawings
Figure 1 is an HPLC profile of form C of pravastatin mesylate before lyophilization.
FIG. 2 is an X-ray powder diffraction spectrum of an amorphous form of Rankine mesylate obtained in example 2.
FIG. 3 is an infrared spectrum of an amorphous form of varenib mesylate obtained in example 2.
FIG. 4 is an HPLC chromatogram of an amorphous form of the Rankine mesylate of example 2.
FIG. 5 is an X-ray powder diffraction spectrum of an amorphous form of Rankine mesylate of example 3.
FIG. 6 is an HPLC chromatogram of an amorphous form of the Rankine mesylate of example 3.
FIG. 7 is an X-ray powder diffraction spectrum of an amorphous form of Rankine mesylate of example 4.
FIG. 8 is an HPLC chromatogram of an amorphous form of the Rankine mesylate of example 4.
FIG. 9 is an X-ray powder diffraction spectrum of an amorphous form of Rankine mesylate of example 5.
FIG. 10 is an HPLC chromatogram of an amorphous form of the Rankine mesylate of example 5.
FIG. 11 is an HPLC chromatogram of an amorphous form of comparative example 1. RTM.
Detailed Description
Example 1 examination of reaction conditions
Adding the pravastatin mesylate crystal C (5 g) into a three-neck flask, adding a solvent, and selecting parameters from the following:
(1) solvent screening
TABLE 1 solvent screening
And (4) conclusion: purified water is selected as a solvent, the pravastatin mesylate C crystal form can be completely dissolved at the temperature of 20-30 ℃, an organic solvent is not needed, and the method is environment-friendly and saves the cost.
(2) Screening of the amount of purified water
TABLE 2 purified Water usage screening
And (4) conclusion: every 1g of the varlitinib mesylate can select 100-200 mL of purified water as a solvent, and 5g of the varlitinib mesylate preferably selects 550mL of purified water.
(3) Selection of temperature for cooling solution
Stirring for 2-3 hours at 20-30 ℃ until the solution is clear, and cooling after the solution is clear, wherein the cooling temperature is selected as follows:
TABLE 3 Cooling temperature screening
And (4) conclusion: the dissolved and cleaned system can be completely solidified at the temperature of-5-0 ℃, and no obvious liquid or cementing solid is generated.
(4) Selecting freeze-drying time and temperature:
and when all solvents in the system are solidified into solids, placing the solids in a freeze dryer, setting the temperature of the freeze dryer to be-5-0 ℃ according to the freezing point of water and the solidification temperature of the dissolved clear system, and starting a vacuum pump until the solids are powdery.
Table 4 lyophilization time screening
And (4) conclusion: the freeze-drying time is less than 9h, a small amount of ice cakes exist in the system, and a large amount of foamy solids appear, so that freeze-drying cannot be carried out. Therefore, the freeze-drying time is set to be 9-12 h to complete freeze-drying.
Example 2
Adding 5g of pravatinib mesylate crystal C into a three-neck flask, adding 550ml of purified water, stirring at 20-30 ℃ for 2-3 hours until the crystal is clear, cooling to-5-0 ℃ after the crystal is clear, placing the solid into a freeze dryer when all solvents in the system are solidified into the solid, setting the temperature of the freeze dryer to-5-0 ℃, starting a vacuum pump, and freeze-drying for 9-12 hours until the solid is powdery. And after freeze-drying is finished, taking out the solid powder, placing the solid powder in a vacuum drying oven, setting the temperature of the drying oven to be 50-55 ℃, controlling the vacuum degree to be less than-0.09 MPa, carrying out vacuum drying for 10-12 hours, and collecting to obtain 4.8g of the amorphous matter of the Ranuncutinib mesylate. The purity was 99.796%, and the water content was 0.32%. The powder X-ray diffraction pattern is shown in FIG. 2, the infrared absorption spectrum is shown in FIG. 3, and the HPLC pattern is shown in FIG. 4.
Example 3
Adding 5g of pravatinib mesylate crystal C into a three-neck flask, adding 550ml of purified water, stirring at 20-30 ℃ for 2-3 hours until the crystal is clear, cooling to-10-5 ℃ after the clear solution is dissolved, placing the solid into a freeze dryer when all solvents in the system are solidified into the solid, setting the temperature of the freeze dryer to-5-0 ℃, starting a vacuum pump, and freeze-drying for 9-12 hours until the solid is powdery. And after freeze-drying is finished, taking out the solid powder, placing the solid powder in a vacuum drying oven, setting the temperature of the drying oven to be 50-55 ℃, controlling the vacuum degree to be less than-0.09 MPa, carrying out vacuum drying for 10-12 hours, and collecting to obtain 4.7g of amorphous matter of the Ranuncutinib mesylate. The purity was 99.797%, and the water content was 0.35%. The powder X-ray diffraction pattern is shown in FIG. 5, and the HPLC pattern is shown in FIG. 6.
Example 4
Adding the Ranuncutinib mesylate crystal C (5 g) into a three-neck flask, adding 1100ml of purified water, stirring at 20-30 ℃ for 2-3 hours until the crystal is clear, cooling to-10 to-5 ℃ after the crystal is clear, placing the solid into a freeze dryer when all solvents in the system are solidified into the solid, setting the temperature of the freeze dryer to-5-0 ℃, starting a vacuum pump, and freeze-drying for 9-12 hours until the solid is powdery. And after freeze-drying is finished, taking out the solid powder, placing the solid powder in a vacuum drying oven, setting the temperature of the drying oven to be 50-55 ℃, controlling the vacuum degree to be less than-0.09 MPa, carrying out vacuum drying for 10-12 hours, and collecting to obtain 4.8g of the amorphous matter of the Ranuncutinib mesylate. The purity was 99.795%, and the water content was 0.34%. The powder X-ray diffraction pattern is shown in FIG. 7, and the HPLC pattern is shown in FIG. 8.
Example 5
Adding the Ranuncutinib mesylate crystal C (5 g) into a three-neck flask, adding 1000ml of purified water, stirring at 20-30 ℃ for 2-3 hours until the crystal is clear, cooling to-5-0 ℃ after the crystal is clear, placing the solid into a freeze dryer when all solvents in the system are solidified into the solid, setting the temperature of the freeze dryer to-5-0 ℃, starting a vacuum pump, and freeze-drying for 9-12 hours until the solid is powdery. And after freeze-drying is finished, taking out the solid powder, placing the solid powder in a vacuum drying oven, setting the temperature of the drying oven to be 50-55 ℃, controlling the vacuum degree to be less than-0.09 MPa, carrying out vacuum drying for 10-12 hours, and collecting to obtain 4.6g of amorphous matter of the Ranuncutinib mesylate. The purity was 99.793%, and the water content was 0.38%. The powder X-ray diffraction pattern is shown in FIG. 9, and the HPLC pattern is shown in FIG. 10.
Comparative example 1 preparation of amorphous form by the method of example 4 of reference patent CN113087666A
Adding 50g of pravatinib mesylate crystal form C into 3.5L of a tert-butyl alcohol/water mixed solution at a ratio of 1:2, stirring and dissolving the mixture clearly at 15-25 ℃, filtering, collecting filtrate, freeze-drying the filtrate, pre-freezing the filtrate for 4h at-45 ℃, drying the filtrate at a vacuum degree of 10 Pa for one time, heating the filtrate to-10 ℃ for 4h, maintaining the filtrate for 12h, heating the filtrate for 2h to 0 ℃ for 12h, heating the filtrate for 2h to 10 ℃ for 24h, analyzing the vacuum degree of 10 Pa, heating the filtrate to 20 ℃ for 4h, heating the filtrate to 35 ℃ for 4h, and maintaining the filtrate for 4h to obtain 48g of a light yellow sponge solid with the water content of 0.40 percent and the relative purity of 99.764 percent. The HPLC chromatogram is shown in FIG. 11.
Example 6 dissolution examination
The amorphous form obtained in example 2 and comparative example 1 was used as a raw material to prepare a varenib mesylate capsule, and the dissolution rate was measured, and the formulation composition was shown in table 5.
TABLE 5 prescription of capsule
Group A: adding amorphous matter of the Ranuncutinib mesylate in the embodiment 2, calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, mannitol and microcrystalline cellulose with the pH value of 101 into a self-sealing bag, manually mixing for 5min, pouring the material into a tray, adding a prescribed amount of purified water, manually granulating, drying the wet soft material in a forced air drying oven at the temperature of 65 ℃ until the water content is less than or equal to 3.0%, taking out the dry soft material, sieving the dry soft material with a 20-mesh sieve for finishing granules, filling the granules into the self-sealing bag, adding a prescribed amount of talcum powder and the microcrystalline cellulose with the pH value of 102, manually mixing for 5min, and filling into a No. 4 HPMC hollow capsule.
Group B: adding amorphous matter of the Ranuncutinib mesylate comparative example 1, calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, mannitol and microcrystalline cellulose with the pH value of 101 into a self-sealing bag, manually mixing for 5min, pouring the materials into a tray, adding a prescribed amount of purified water, manually granulating, drying the wet soft material in a forced air drying oven at the temperature of 65 ℃ until the water content is less than or equal to 3.0%, taking out the dry soft material, sieving the dry soft material with a 20-mesh sieve for finishing granules, filling the granules into the self-sealing bag, adding a prescribed amount of talcum powder and the microcrystalline cellulose with the pH value of 102, manually mixing for 5min, and filling into a No. 4 HPMC hollow capsule.
The above samples were tested for dissolution as follows, respectively, and the results are shown in Table 6.
Dissolution medium: pH4.5 (1L medium preparation method: 2.99g sodium acetate trihydrate and 14ml2mol/L acetic acid solution, adding water to 1000ml, measuring pH, adjusting to pH4.5 with acetic acid)
Volume of medium: 900ml
The method comprises the following steps: paddle method and sedimentation basket
Rotating speed: 75rpm
Sampling time points are as follows: 10min, 15min, 20min, 30min, 45min, 60min, 90min, 120min
Liquid phase sampling mode: 5ml of the filtrate is filtered by a 0.45-umPP filter head, 4ml of the primary filtrate is discarded, and a secondary filtrate is obtained. 5ml of rehydration solution
An ultraviolet sampling mode: 10ml of the filtrate is filtered by a 0.45-umPP filter head, 4ml of the primary filtrate is discarded, and a secondary filtrate is obtained. 10ml of rehydration solution
TABLE 6 dissolution data statistics
Example 7 solubility examination
The amorphous materials obtained in example 2 and comparative example 1 were examined for solubility in sequence with reference to the general example of the chinese pharmacopoeia, year 2020, and the results are shown in table 7.
Table 7 solubility data statistics
And (4) conclusion: comparing with tables 6 and 7, compared with the samples obtained by the existing preparation method of the amorphous matter of the varlitinib mesylate, the amorphous matter prepared by the invention has the advantages of improved dissolution rate and solubility, and is beneficial to improving the bioavailability.
The invention discloses a preparation method of an amorphous substance of a lunfacitinib salt. The technical personnel can modify the technological parameters appropriately to realize the method by taking the contents of the invention as reference. It is expressly intended that all such substitutions and modifications which are obvious to those skilled in the art are deemed to be included herein. While the process of the present invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations and modifications in the application of the process described herein, or appropriate variations and combinations thereof, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
Claims (7)
1. A preparation method of amorphous matter of varlitinib mesylate is characterized in that:
dissolving the crystalline form C of the pravastatin mesylate by using purified water at the temperature of 20-30 ℃, stirring and dissolving, cooling a pravastatin mesylate solution, setting the freeze-drying temperature and the freeze-drying time when the solution is completely solidified into a solid, and putting the solid into a freeze-dryer for freeze-drying to be powdery; and taking out the powdery solid, and placing the powdery solid in a vacuum drying oven for vacuum drying to obtain the amorphous matter of the methane sulfonic acid lunvatinib.
2. The method for preparing the amorphous matter of the pravastatin mesylate according to claim 1, wherein the mass-to-volume ratio of the pravastatin mesylate to the purified water in which the pravastatin mesylate is dissolved is selected from 1:100 to 1: 200.
3. The method for preparing the amorphous matter of the pravastatin mesylate according to claim 1, wherein the pravastatin mesylate solution after stirring and clearing is cooled at-10 to 0 ℃.
4. The method for preparing an amorphous form of a salt of ranvatinib as claimed in claim 3, wherein the ranvatinib mesylate solution after stirring and clearing is cooled at-5 to 0 ℃.
5. The method for preparing an amorphous form of varenib mesylate according to claim 1, wherein the lyophilization temperature is selected from-5 to 0 ℃.
6. The method for preparing the amorphous matter of the varlitinib mesylate according to claim 1, wherein the freeze-drying time is selected from 9 to 12 hours.
7. A process for preparing an amorphous form of pravastatin mesylate according to claim 1, wherein: the amorphous matter of the pravastatin mesylate is radiated by Cu-Kalpha, and has no sharp derivatives in an X-ray powder diffraction spectrum expressed by 2 thetaSpraying peak, infrared absorption spectrum obtained by KBr tablet measurement at 1050.384cm-1、1192.971cm-1、1454.558 cm-1、1647.389 cm-1、3304.492 cm-1Has an absorption peak.
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