Method for analyzing naproxen-proline eutectic based on broadband terahertz spectrum

Abstract

The invention provides a method for analyzing naproxen-proline eutectic based on broadband terahertz spectroscopy, and belongs to the technical field of pharmaceutical eutectic analysis. The analysis method provided by the invention comprises the following steps: preparing a naproxen-proline eutectic crystal; carrying out broadband terahertz spectrum analysis on the naproxen-proline eutectic crystal to obtain a broadband terahertz spectrum analysis result; and carrying out optimization and energy calculation on the naproxen-proline eutectic structure based on the broadband terahertz spectrum analysis result to obtain an analysis result of the naproxen-proline eutectic. According to the analysis method, the broadband terahertz spectrum technology is combined with quantum chemistry calculation, eutectic terahertz spectrum change caused by temperature is explained, and the corresponding relation between an experimental result and theoretical prediction is enhanced; and the reliability of quantum chemical calculation in the aspects of identifying the vibration mode and understanding the intermolecular non-covalent interaction principle is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug co-crystal analysis, and in particular to an analysis method for NAP-PRO co-crystal based on broadband terahertz spectroscopy. Background Art

[0002] Pharmaceutical cocrystals are a commonly used technique to modify and modulate the physicochemical properties of active pharmaceutical ingredients (APIs), including solubility, stability, and permeability. This approach is particularly effective for improving the solubility of poorly soluble nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen (NAP), and flurbiprofen, all of which belong to class II of the Biopharmaceutics Classification System (BCS). By selecting appropriate cocrystal formers (CCFs), higher bioavailability can be achieved while maintaining the therapeutic properties of these APIs. Among NSAIDs, naproxen is widely used in clinical applications due to its longer half-life, better gastrointestinal tolerability, and lower cardiovascular risk. Currently, studies have shown that amino acids can form cocrystals with naproxen, including D-tyrosine, L-alanine, and proline (PRO).

[0003] In order to fully understand the impact of cocrystals, the molecular interactions that drive this process must be studied. A variety of techniques have been used in the analysis of pharmaceutical cocrystals, including powder X-ray diffraction (PXRD), Raman spectroscopy, and Fourier transform infrared spectroscopy (FTIR). Given that the energy level of terahertz (THz) photons matches the potential of non-covalent interactions, the application of THz spectroscopy provides a unique opportunity to explore the role of molecular interactions in controlling the behavior of cocrystals.

[0004] Terahertz time domain-spectroscopy (THz-TDS) is capable of spectral characterization, process monitoring, and feature analysis. However, its limitations in frequency range may hinder the comprehensive analysis of cocrystals. Therefore, it is necessary to collect its broadband THz spectra over a wider range (1-18 THz), which will help to more fully understand the driving force behind the pharmaceutical cocrystal phenomenon. Qualitative description of the spectrum can provide an intuitive understanding of the vibrational modes, but it is not sufficient to fully reveal the vibrational properties of the molecule.

[0005] Based on this, it is of great practical significance to provide an analysis method for naproxen-proline cocrystal based on broadband terahertz spectroscopy. Summary of the invention

[0006] The object of the present invention is to provide an analysis method for naproxen-proline cocrystal based on broadband terahertz spectroscopy, aiming to solve the technical problem that terahertz spectroscopy in the prior art is incomplete in cocrystal analysis due to the limitation of frequency range.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] The present invention provides a method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy, comprising the following steps:

[0009] Preparation of naproxen-proline cocrystals;

[0010] Performing broadband terahertz spectroscopy analysis on the naproxen-proline cocrystal to obtain broadband terahertz spectroscopy analysis results;

[0011] Based on the broadband terahertz spectroscopy analysis results, the naproxen-proline cocrystal structure is optimized and the energy is calculated to obtain the analysis results of the naproxen-proline cocrystal.

[0012] Furthermore, the purity of naproxen in the naproxen-proline cocrystal is greater than 98.0%, the purity of proline is greater than 99.8%, and the dosage ratio of naproxen to proline is 1:1.

[0013] Furthermore, after the naproxen-proline co-crystal is prepared, it is mixed with the cycloolefin copolymer and then ground to prepare the naproxen-proline co-crystal preparation to be analyzed.

[0014] Furthermore, the mass ratio of the naproxen-proline cocrystal to the cycloolefin copolymer is 1:4.

[0015] Furthermore, the naproxen-proline cocrystal is prepared by liquid-assisted grinding.

[0016] Furthermore, the broadband terahertz spectroscopy analysis is to analyze the naproxen-proline cocrystal using broadband terahertz spectroscopy and FTIR technology.

[0017] Furthermore, the broadband terahertz spectrum adopts TAS7400SU system with a frequency range of 1.0 to 4.0 THz.

[0018] Furthermore, the FTIR technique uses a Bruker V80v spectrometer with a frequency range of 1.0 to 18.0 THz.

[0019] Furthermore, the energy calculation is performed by means of a hyperfine mass setting.

[0020] The present invention also provides the application of the analysis method for naproxen-proline cocrystal based on broadband terahertz spectroscopy described in the above technical solution in the analysis of naproxen-proline cocrystal.

[0021] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0022] The method of the present invention adopts broadband terahertz (THz) spectroscopy technology, combined with quantum chemical calculation, to carry out a detailed analysis of various characteristic absorption peak vibration modes of naproxen-proline cocrystal, and explores the origin of these vibrations by examining the changes in intermolecular hydrogen bonds; in order to match the experimental results with the calculation results, a variable temperature experiment is carried out to explore the temperature-dependent behavior of the THz spectrum of the naproxen-proline cocrystal; the changes in the THz spectrum of the cocrystal caused by temperature are explained, the correspondence between the experimental results and the theoretical predictions is enhanced, and the reliability of quantum chemical calculation in identifying vibration modes and understanding the principle of non-covalent interactions between molecules is improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a schematic diagram of the result of step (3) described in Example 1 of the present invention;

[0024] in: Figure 1 (a) is a comparison of the PXRD patterns of naproxen-proline cocrystal and the crystal structure calculated from CCDC;

[0025] Figure 1 (b) is a structural specific analysis diagram of naproxen-proline co-crystal relative to its parent compound;

[0026] Figure 1 (c) is the THz absorption spectrum of naproxen-proline cocrystal obtained using FTIR and THz-TDS system;

[0027] Figure 2 A comparison diagram of the experimental spectrum and the calculated spectrum obtained in Example 1 of the present invention;

[0028] Figure 3 The vibration mode diagram of the naproxen-proline co-crystal at 5.10 THz and 11.19 THz described in Example 1 of the present invention;

[0029] in: Figure 3 (a) is the vibration mode diagram of naproxen-proline cocrystal at 5.10 THz;

[0030] Figure 3 (b) is the vibration mode diagram of naproxen-proline cocrystal at 11.19 THz;

[0031] Figure 4 This is a trend diagram of the FWHM of the naproxen-proline co-crystal obtained in Example 1 of the present invention at 5.10 THz and 11.19 THz absorption peaks changing with temperature. DETAILED DESCRIPTION

[0032] The present invention provides a method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy, comprising the following steps:

[0033] Preparation of naproxen-proline cocrystals;

[0034] Performing broadband terahertz spectroscopy analysis on the naproxen-proline cocrystal to obtain broadband terahertz spectroscopy analysis results;

[0035] Based on the broadband terahertz spectroscopy analysis results, the naproxen-proline cocrystal structure is optimized and the energy is calculated to obtain the analysis results of the naproxen-proline cocrystal.

[0036] Preparation of naproxen-proline cocrystals (NAP-PRO cocrystals);

[0037] The present invention preferably purchases naproxen (NAP) with a purity greater than 98% from Tokyo Chemical Industry (TCI, Shanghai, China), methanol with a purity greater than 99.8% and proline (PRO) with a purity greater than 99% from Shanghai Aladdin Biochemical Technology Co., Ltd. (Aladdin, Shanghai, China), and cyclic olefin copolymer (COC) from the experimental factory of Shanghai Institute of Nuclear Research.

[0038] In the present invention, the purity of naproxen in the NAP-PRO cocrystal is >98.0%, the purity of proline is >99.8%, and the dosage ratio of naproxen to proline is 1:1.

[0039] The NAP-PRO eutectic of the present invention is preferably prepared by liquid-assisted grinding (LAG) method, using a ball mill (Retsch MM400, Germany) to mix in a stoichiometric ratio of 1:1, adding 5 μL of methanol, and the mixture powder is ball-milled at a frequency of 30 Hz for 60 minutes, and then the NAP-PRO eutectic and COC are mixed and ground at a mass ratio of 1:4 for 5 minutes. The uniform mixture is then placed in a tableting device and pressed at a pressure of 10 MPa for 5 minutes to form a round tablet with a diameter of 13 mm and a thickness of 1 mm, for subsequent broadband terahertz analysis.

[0040] In the present invention, after the NAP-PRO eutectic is prepared, it is mixed with COC and then ground to prepare the NAP-PRO eutectic preparation to be analyzed.

[0041] In the present invention, the mass ratio of the NAP-PRO eutectic to COC is 1:4.

[0042] In the present invention, the NAP-PRO co-crystal is prepared by liquid-assisted grinding.

[0043] Performing broadband terahertz spectroscopy analysis on the NAP-PRO eutectic to obtain broadband terahertz spectroscopy analysis results;

[0044] In the present invention, the broadband terahertz spectroscopy analysis is to analyze the NAP-PRO eutectic using terahertz time-domain spectroscopy and FTIR technology.

[0045] The vibration behavior of NAP-PRO eutectic was studied by combining broadband terahertz spectroscopy and FTIR technology; broadband terahertz spectroscopy used TAS7400SU system (Advantest Corporation, Japan), which covers the frequency range of 1.0-4.0THz and the resolution is 1.9GHz. During the entire measurement process, dry air was circulated through the optical path to ensure a relative humidity of 1.5% and a temperature of 295K; FTIR measurement used a BrukerV80v spectrometer (Bruker Corporation, USA), which covers the frequency range of 1.0-18.0THz and the resolution is 2.4GHz. Temperature control uses MercuryiTC (OxfordInstruments NanoScience, UK), and the temperature range can be adjusted from room temperature to 4K to obtain broadband terahertz spectroscopy analysis results.

[0046] In the present invention, the broadband terahertz spectrum adopts TAS7400SU system with a frequency range of 1.0 to 4.0 THz.

[0047] In the present invention, the FTIR technique uses a Bruker V80v spectrometer with a frequency range of 1.0 to 18.0 THz.

[0048] Based on the broadband terahertz spectrum analysis results, the NAP-PRO eutectic structure is optimized and the energy is calculated to obtain the analysis results of the NAP-PRO eutectic.

[0049] Based on the above broadband terahertz spectroscopy analysis results, the Cambridge Sequential Total Energy Package (CASTEP) module in Accelrys Materials Studio software was used to optimize the geometry and calculate the energy of the eutectic structure. The initial structural data for the eutectic theoretical calculation came from the Cambridge Crystallographic Data Centre (CCDC), with the identification number 1861021. In the density functional theory (DFT) simulation, the plane wave-based generalized gradient approximation (GGA) functional was used, combined with the Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional for crystal characterization. In order to thoroughly optimize the geometry of the crystal structure, the ultrafine setting was selected for the energy calculation of the eutectic. The Broyden-Fletcher-Goldfarb-Shanno (BFGS) algorithm was used for lattice optimization while keeping the unit cell mass constant.

[0050] Grimme dispersion correction was introduced in the DFT-Dispersion correction second version (DFT-D2) scheme, and the gauge conservation pseudopotentials available in CASTEP were used, with the plane wave basis set cutoff set to 830 eV. In order to accurately represent the electronic states in the crystal, a 2×3×1 Monkhorst-Pack grid was used for Brillouin zone sampling, while the fast Fourier transform (FFT) grid size was configured to 120×100×450 to efficiently accelerate the calculation. The total energy converged to 5.0×10 -6 eV·atom -1 , the maximum interatomic force is The maximum displacement is

[0051] In the present invention, the energy calculation is performed by a hyperfine setting.

[0052] The present invention also provides the application of the analysis method of NAP-PRO eutectic based on broadband terahertz spectroscopy described in the above technical solution in the analysis of NAP-PRO eutectic.

[0053] In the present invention, unless otherwise specified, the required raw materials for preparation are all commercially available products well known to those skilled in the art.

[0054] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0055] Example 1

[0056] (1) Raw material preparation: Naproxen (NAP) with a purity greater than 98% was purchased from Tokyo Chemical Industry (TCI, Shanghai, China), methanol with a purity greater than 99.8% and proline (PRO) with a purity greater than 99% were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. (Aladdin, Shanghai, China), and cyclic olefin copolymer (COC) was purchased from the experimental plant of Shanghai Institute of Nuclear Research;

[0057] (2) Preparation of NAP-PRO cocrystals: NAP-PRO cocrystals were prepared by liquid-assisted grinding (LAG) method. A ball mill (Retsch MM400, Germany) was used to mix the cocrystals in a stoichiometric ratio of 1:1. After adding 5 μL of methanol, the mixture powder was ball-milled at a frequency of 30 Hz for 60 min. Then, NAP-PRO cocrystals and COC were mixed and ground at a mass ratio of 1:4 for 5 min. The homogeneous mixture was then placed in a tablet press and pressed at a pressure of 10 MPa for 5 min to form round tablets with a diameter of 13 mm and a thickness of 1 mm for subsequent broadband terahertz analysis.

[0058] (3) Perform broadband terahertz spectroscopy analysis: Combine terahertz time-domain spectroscopy and FTIR technology to study the vibration behavior of NAP-PRO eutectic; broadband terahertz spectroscopy uses the TAS7400SU system (Advantest Corporation, Japan), which covers a frequency range of 1.0-4.0 THz with a resolution of 1.9 GHz. During the entire measurement process, dry air is circulated through the optical path to ensure a relative humidity of 1.5% and a temperature of 295 K; FTIR measurements use a Bruker V80v spectrometer (Bruker Corporation, USA), which covers a frequency range of 1.0-18.0 THz with a resolution of 2.4 GHz, and temperature control uses Mercuryi TC (Oxford Instruments NanoScience, UK), and the temperature range can be adjusted from room temperature to 4 K to obtain broadband terahertz spectroscopy analysis results;

[0059] (4) Structural optimization and energy calculation: Based on the above broadband terahertz spectroscopy analysis results, the Cambridge Sequential Total Energy Package (CASTEP) module in Accelrys Materials Studio software was used to optimize the geometric structure and calculate the energy of the eutectic structure. The initial structural data for the eutectic theoretical calculation came from the Cambridge Crystallographic Data Centre (CCDC), with the identification number 1861021. In the density functional theory (DFT) simulation, the plane wave-based generalized gradient approximation (GGA) functional was used, combined with the Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional for crystal characterization. In order to thoroughly optimize the geometry of the crystal structure, the ultrafine quality setting was selected for the energy calculation of the eutectic. The Broyden-Fletcher-Goldfarb-Shanno (BFGS) algorithm was used for lattice optimization while keeping the unit cell mass constant.

[0060] Grimme dispersion correction was introduced in the DFT-Dispersion correction second version (DFT-D2) scheme, and the gauge conservation pseudopotentials available in CASTEP were used, with the plane wave basis set cutoff set to 830 eV. In order to accurately represent the electronic states in the crystal, a 2×3×1 Monkhorst-Pack grid was used for Brillouin zone sampling, while the fast Fourier transform (FFT) grid size was configured to 120×100×450 to efficiently accelerate the calculation. The total energy converged to 5.0×10 -6 eV·atom -1 , the maximum interatomic force is The maximum displacement is

[0061] The tests and analyses involved in Example 1 are as follows:

[0062] (1) After the preparation of the NAP-PRO eutectic described in step 2 of Example 1 was completed, broadband terahertz spectroscopy analysis was performed on it, and the PXRD pattern of the prepared eutectic was compared with the crystal structure calculated from CCDC. The results are as follows: Figure 1 (a) shown; based on Figure 1 (a) It can be seen that step (2) completes the preparation of NAP-PRO cocrystal; on this basis, THz spectroscopy is used to further explore the structural specificity of the cocrystal relative to its parent compound. The results are as follows Figure 1 As shown in (b), based on Figure 1 (b) It can be seen that proline exhibits a broad absorption peak at about 2.75 THz, while naproxen shows obvious characteristic absorption peaks at 2.25 and 3.22 THz. In contrast, the NAP-PRO cocrystal shows unique spectral fingerprints at 1.91, 2.30 and 3.69 THz. These features are not a simple superposition of the parent spectrum, indicating a new molecular arrangement and revealing its structural characteristics different from those of the parent compound; further, the THz absorption spectrum of the NAP-PRO cocrystal was obtained using the FTIR and THz-TDS system, as shown in Figure 2. Figure 1 (c) shows that based on Figure 1 (c) It can be seen that clear absorption peaks were observed for NAP-PRO eutectic at 2.29, 3.66, 4.91, 5.84, 7.20, 7.61, 8.98, 9.94, 10.95, 11.99, 12.88, 14.25, 14.93, 15.66, 16.70 and 17.19 THz. In order to ensure the reliability of the data, the data in the 1-4 THz range were compared with those measured by the THz-TDS system, and the results showed a high degree of consistency. Collecting broadband THz fingerprint spectra of NAP-PRO eutectic facilitates specific identification and label-free detection.

[0063] (2) To further analyze the intermolecular interactions, quantum chemical calculations were used to simulate the THz absorption spectrum of the NAP-PRO cocrystal. These calculations are usually performed under ideal conditions, such as a temperature of 0 K, to exclude interference from thermal motion and other external factors. In our experimental study of the THz spectral characteristics of the cocrystal, the measurements were performed at a temperature of 300 K. The key characteristic absorption peaks are matched to specific vibration modes in Table 1. The results are shown in Table 1. Figure 2 As shown, there is an obvious difference in peak frequency between the experimental spectrum (red curve) at 300K and the theoretically calculated spectrum (purple curve). As the temperature decreases, the absorption peak changes of NAP-PRO cocrystal are reflected in the following aspects:

[0064] First, almost all absorption peaks show a trend of amplitude enhancement. This phenomenon is due to the fact that at lower temperatures, the molecular thermal motion is reduced, resulting in a decrease in the proportion of molecules with sufficient energy to overcome the energy barrier. Therefore, the number of molecules at lower energy levels increases, thereby enhancing the absorption process. Secondly, the restriction of molecular vibration and rotational freedom at lower temperatures causes the spectral peaks to become sharper and the structure to be more refined. This is because lower temperatures limit the distribution of molecular velocities, thereby weakening the Doppler broadening effect and ultimately reducing the line width of the spectral peaks;

[0065] In addition, some absorption peaks show a blue shift in frequency, for example, the 4.91THz and 10.95THz peaks at 300K shift to 5.07THz and 11.19THz at 30K, respectively. This frequency shift is believed to be caused by the thermal expansion of the lattice volume and the anharmonicity of the potential energy curve when the temperature decreases;

[0066] Finally, during the cooling process, some single broad peaks split into two narrower peaks. The appearance of these new peaks may be due to the enhanced molecular thermal motion at higher temperatures, which masks some inherent vibration modes of the eutectic. As the temperature decreases, these vibration modes gradually emerge. Compared with the THz spectrum at 300K, the spectrum at 30K shows several new absorption peaks, especially at 5.51THz, 9.10THz and 12.24THz, revealing the spectral features hidden at room temperature.

[0067] These changes further illustrate the significant effect of temperature on the intermolecular interactions of NAP-PRO cocrystals. Through these detailed temperature-dependent experiments, we can gain a deeper understanding of the structure and kinetic behavior of cocrystals at different temperatures, thus providing an important scientific basis for the design and optimization of cocrystal materials. These findings not only help reveal the stabilization mechanism of cocrystals, but also provide new ideas for the development of pharmaceutical materials with better physicochemical properties.

[0068] Table 1 Comparison and distribution of vibration modes in experimental and theoretical THz spectra

[0069]

[0070]

[0071] ν (rotation), r (sway), ω (swing), t (translation), l (balance vibration), s (shear vibration), LSC (long side chain in NAP), -CH3 (methyl in NAP), -NH2 + -(quaternary ammonium group in PRO), -CH2-(methylene group in PRO) and BR (benzene ring in NAP).

[0072] (3) Since the vibration modes of NAP-PRO eutectic at 5.10 THz and 11.19 THz show more obvious shifts and characteristic changes, they are selected as examples for further analysis. The results are as follows: Figure 3 As shown, based on Figure 3 It can be seen that a hydrogen bond is formed between the carboxyl hydrogen atom of naproxen and the carboxylate oxygen atom of proline, which may be one of the important reasons for the formation of the eutectic. Figure 3 In (a), the vibration mode at 5.10 THz is mainly composed of the collective vibration of the molecule and the rotation of the methyl group in the naproxen molecule. The vibration change of the hydroxyl group in naproxen leads to the change of the length and direction of the hydrogen bond, which is another aspect that affects the characteristic absorption peak. At 11.19 THz, Figure 3 (b) shows that the main vibration of proline comes from the rocking motion of the methylene group in the amino group, while the naproxen molecule has almost no vibration. In this vibration mode, no changes in hydrogen bonds are observed.

[0073] (4) The trend of the FWHM of the NAP-PRO eutectic at 5.10 THz and 11.19 THz absorption peaks with temperature was investigated. The results are as follows: Figure 4 as shown; Figure 4 As shown in (a), the figure shows the trend of FWHM of 5.10THz and 11.19THz absorption peaks changing with temperature. The broadening of FWHM is affected by many factors, among which the main factors include natural broadening, collision broadening and Doppler broadening. Under the combined effect of these factors, the temperature-dependent change of FWHM follows a Gaussian distribution pattern; the temperature-related FWHM is determined by Gaussian fitting, as shown in Figure 4 (a). It is affected by many factors and follows the following quadratic fitting form:

[0074] FWHM(T)=aT 2 +bT+c

[0075] Among them, a, b, c are three constants, and the units are THzK -2 , THzK-1 and THz. Since the number of phonons n is approximately proportional to the thermodynamic temperature, the correlation shows that the broadening is proportional to n 2 The fitting parameters are recorded in Table 2.

[0076] Table 2 Figure 4 (a) Fitting parameter record table

[0077] Mode / THz <![CDATA[a / (THzK -2 )]]> <![CDATA[b / (THzK -1 )]]> c / THz <![CDATA[R 2 ]]> 5.10 <![CDATA[1.89×10 -6 ]]> <![CDATA[-3.32×10 -5 ]]> 0.37 0.99476 11.19 <![CDATA[2.90×10 -6 ]]> <![CDATA[4.42×10 -5 ]]> 0.40 0.99571

[0078] Figure 4 (a) Relationship between the FWHM of the two vibration modes in NAP-PRO eutectic and temperature and the quadratic fitting curve. Figure 4 (b) Correlation diagram of the characteristic peak positions at 5.10 THz (red squares) and 11.19 THz (black squares) versus temperature. The black and red curves represent the fitting based on the Bose-Einstein distribution.

[0079] Figure 4 (b) is the fitting curve of the absorption peak frequency variation with temperature in the above two characteristic modes. Since phonons are bosons, their temperature dependence may follow the Bose-Einstein statistical law. The frequency shift of each observed absorption feature is fitted by the following formula:

[0080]

[0081] Where ω0 is the center frequency of the vibration mode at 0K, and A is a constant. C is the characteristic temperature related to energy. Substituting into equation (1), the parameter fitting of the above two characteristic absorption peaks is recorded in Table 3.

[0082] Table 3 Figure 4 (b) Fitting parameter record table

[0083] Mode / THz <![CDATA[A / (THzK -1 )]]> <![CDATA[ω0 / THz]]> <![CDATA[T C / K]]> <![CDATA[R 2 ]]> 5.10 <![CDATA[1.53×10 -4 ]]> 11.19 357 0.99645 11.19 <![CDATA[7.25×10 -4 ]]> 5.08 155 0.99787

[0084] Parameter T C is related to the energy of the phonon ground state in a particular mode. At two different frequencies T C The differences in can be attributed to the changes in the phonon energy associated with these frequencies. The constant A is indirectly related to the ground state energy through the characteristic temperature, reflecting the energy distribution of vibrational modes at different temperatures and the coupling effect between vibrational modes, which indicates that the energy of the hydrogen bond network in the corresponding crystals may also be similar.

[0085] In summary, the present invention uses broadband THz spectroscopy technology, combined with quantum chemical calculations, to conduct a detailed analysis of the various characteristic absorption peak vibration modes of NAP-PRO eutectics. By examining the changes in intermolecular hydrogen bonds, the origin of these vibrations was explored. In order to match the experimental results with the calculated results, variable temperature experiments were carried out to explore the temperature-dependent behavior of the THz spectrum of the NAP-PRO eutectic. Explaining the changes in the eutectic THz spectrum caused by temperature enhances the correspondence between experimental results and theoretical predictions, and improves the reliability of quantum chemical calculations in identifying vibration modes and understanding the principles of non-covalent interactions between molecules.

[0086] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy, characterized in that: The following steps are involved: Preparation of naproxen-proline cocrystals; Performing broadband terahertz spectroscopy analysis on the naproxen-proline cocrystal to obtain broadband terahertz spectroscopy analysis results; Based on the broadband terahertz spectroscopy analysis results, the naproxen-proline cocrystal structure is optimized and the energy is calculated to obtain the analysis results of the naproxen-proline cocrystal.

2. The method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy according to claim 1, characterized in that: The naproxen purity of the naproxen-proline cocrystal is greater than 98.0%, and the proline purity is greater than 99.8%. The dosage ratio of the naproxen to the proline is 1:

1.

3. The method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy according to claim 1, characterized in that: After the naproxen-proline co-crystal is prepared, it is mixed with the cycloolefin copolymer and then ground to prepare the naproxen-proline co-crystal preparation to be analyzed.

4. The method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy according to claim 3, characterized in that: The mass ratio of the naproxen-proline cocrystal to the cycloolefin copolymer is 1:

4.

5. The method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy according to claim 1, characterized in that: The naproxen-proline cocrystals were prepared by liquid-assisted grinding.

6. The method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy according to claim 1, characterized in that: The broadband terahertz spectroscopy analysis is to analyze the naproxen-proline cocrystal using broadband terahertz spectroscopy and FTIR technology.

7. The method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy according to claim 6, characterized in that: The TAS7400SU system is used, and the frequency range is 1.0 to 4.0 THz.

8. The method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy according to claim 6, characterized in that: The FTIR technique uses a Bruker V80v spectrometer with a frequency range of 1.0 to 18.0 THz.

9. The method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy according to claim 1, characterized in that: The energy calculations were performed with a hyperfine mass setting.

10. Use of the method for analyzing naproxen-proline cocrystal based on broadband terahertz spectroscopy according to any one of claims 1 to 9 in analyzing naproxen-proline cocrystal.

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