Phosphor detection method and application of special impurity I in naproxen bulk drug and preparation

Abstract

The present application relates to the field of drug impurity inspection, and specifically provides a ternary doped system, a method for inspecting special impurity I in naproxen raw drug and preparation, and application. The ternary doped system is doped with ketoprofen, naproxen and special impurity I. The method is based on host-guest doped room temperature phosphorescence technology, and an analysis platform for detecting trace special impurity I in naproxen raw drug with high sensitivity is constructed, with a detection limit as low as 0.05%, meeting the 0.1% inspection limit requirement specified in the pharmacopoeia. The technology can not only realize the limited inspection of the impurity in naproxen granules or tablets through spectral analysis and visual means, but also can be successfully applied to real-time monitoring of dynamic changes of impurities in the production process of different dosage forms. The present application has the advantages of strong specificity, high sensitivity, low reagent consumption and the like, meets the growing demand of the pharmaceutical industry for process analysis technology (PAT) in the impurity inspection process, and has good application value in the quality control of naproxen drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical analysis technology, and specifically to a method for testing related substances in naproxen raw material and preparations. It proposes a phosphorescence analysis method for determining specific impurity I in naproxen using an appropriate amount of a main probe molecule. Background Technology

[0002] Naproxen (S-NAP) is a nonsteroidal anti-inflammatory drug and antirheumatic drug. 6-Methoxy-2-acetylnaphthalene (MANAP, a specific impurity I in naproxen) is an intermediate and photodegradation product in the synthesis of naproxen; therefore, monitoring impurity I is particularly important during the production of naproxen API and formulations. Afterglow is a long-lived luminescence phenomenon, including room-temperature phosphorescence (RTP) and thermally activated delayed fluorescence (TADF), which continue to emit light after the excitation source is removed. Compared to fluorescence, phosphorescence has a longer emission lifetime and a larger Stokes shift due to the involvement of a triplet excited state. This extended emission time significantly improves the signal-to-background ratio (SBR) and detection specificity; therefore, organic phosphorescence has great application potential in high-efficiency organic light-emitting diodes, data encryption, and anti-counterfeiting. Currently, research on RTP is relatively limited in the pharmaceutical field, especially in drug analysis. Reports on phosphorescence behavior related to drug molecules are few, and research on its applications in pharmaceutical analysis is even scarcer. Therefore, long-lived reactive phosphorylation (RTPs) related to drug molecules and their impurities, and their practical applications, especially in impurity detection, still hold great promise for research and development. Thus, exploring RTPs derived from drug molecules and their impurities and developing their practical applications demonstrates innovation and necessity. Host-guest doping is an effective strategy for constructing RTP materials, demonstrating that even trace amounts of phosphorescent guest molecules dispersed in the host matrix still exhibit bright room-temperature phosphorescence. The host material provides a rigid external environment for the guest molecules, restricting their vibration and suppressing triplet nonradiative transitions, preventing phosphorescence quenching caused by water and oxygen. Based on these luminescence principles, room-temperature phosphorescence cannot be generated when the host content is lower than the guest content. Benefiting from the low doping ratio of guest molecules in the host-guest doping system and the characteristic that low host content prevents luminescence, this approach can be applied to the detection of trace impurities in drugs.

[0003] Currently, the pharmacopoeia specifies that the test for special impurities I in naproxen is performed using high performance liquid chromatography (HPLC). Its advantages are high sensitivity and strong specificity, while its disadvantages are: expensive instruments, long and difficult operation time, high requirements for operators, and large amount of organic solvents used.

[0004] To address the aforementioned issues, developing a technology that simplifies the detection process, improves detection sensitivity and specificity, and can directly utilize the signal differences caused by the photoselectivity of drugs and impurities for quantitative or limited impurity detection has become an urgent problem to be solved. Summary of the Invention

[0005] In view of this, the purpose of this invention is to address the problems of existing methods for detecting specific impurities I in naproxen, which are complex to operate, require a large amount of organic reagents, and have a long operation time. This invention provides a method for detecting specific impurities I in naproxen raw materials and their preparations based on host-guest doping room temperature phosphorescence spectroscopy analysis technology.

[0006] Therefore, one objective of this invention is to provide a ternary doping system comprising doping with ketoprofen, naproxen, and a specific impurity I, wherein the specific impurity I is 6-methoxy-2-acetylnaphthalene. The doping method can be either a melt method or a milling method. The general molecular formulas of naproxen, specific impurity I, and ketoprofen are as follows:

[0007]

[0008] Preferably, the mass ratio of ketoprofen to naproxen is 1:5.

[0009] Preferably, the mass ratio of ketoprofen, naproxen, and special impurity I is 200:1000:0 ~ 32.

[0010] Furthermore, the mass ratio of ketoprofen, naproxen, and special impurity I is 200:1000:1.

[0011] The second objective of this invention is to provide a method for detecting a specific impurity I in naproxen based on host-guest doping and room-temperature phosphorescence. The method includes using ketoprofen as the host material and naproxen specific impurity I as the guest material, wherein the specific impurity I is 6-methoxy-2-acetylnaphthalene. The doping system is obtained by melting or grinding and mixing, and then the room-temperature phosphorescence signal under 365 nm ultraviolet light excitation is detected to achieve qualitative or quantitative analysis of specific impurity I in naproxen.

[0012] Preferably, the amount of ketoprofen used is between that of naproxen and special impurity I. The amount refers to mass.

[0013] Preferably, the mass ratio of ketoprofen to naproxen is 1:5.

[0014] Furthermore, the content of specific impurity I in naproxen is obtained through the linear equation y = 0.5072x + 2.8156, where x is the logarithm of the content of specific impurity I multiplied by 100, i.e., lg(content of specific impurity I × 100), and the range of x is 0.05 ~ 3.2. y is the ratio I1 / I0 of the phosphorescence intensity of 540 nm under 365 nm ultraviolet light excitation of molten doping, where I1 is the phosphorescence intensity of the doped system, I0 is the background phosphorescence intensity without specific impurity I, and I1 / I0 is the ratio of I1 to I0.

[0015] For example, ketoprofen is added to naproxen raw material or formulation, and a doped system is obtained by melting or grinding. Then, its room-temperature phosphorescence signal under 365 nm ultraviolet light excitation is detected. Preferably, the phosphorescence spectrum is obtained by spectrometer detection, and further, the phosphorescence intensity at 540 nm is obtained. If a room-temperature phosphorescence signal is generated, it indicates the presence of a specific impurity I. The content of specific impurity I in naproxen is obtained according to the ratio of phosphorescence intensity I1 / I0 and the linear equation y=0.5072x+2.8156.

[0016] The third objective of this invention is to provide the application of the above method in the dynamic monitoring of impurities during the production of naproxen preparations, including the addition of ketoprofen for grinding after the granulation or tableting process during the production of tablets or granules, and real-time monitoring of the content of special impurity I by changes in phosphorescence intensity.

[0017] Furthermore, the visual detection limit for special impurity I in the formulation is 0.1%, enabling rapid on-site screening by visually observing changes in the phosphorescence signal.

[0018] The detection sensitivity (LOD) of naproxen specific impurity I using the above method meets the pharmacopoeia requirements, the single detection time is ≤10 minutes, and chromatographic separation is not required.

[0019] RTP systems in host-guest doping mode are not simply two-component mixtures; they require the dispersion of trace amounts of the guest substance within the host matrix. Therefore, the content of the host substance is typically much greater than that of the guest substance to exhibit good phosphorescence emission properties. In this invention, KPF is melt-doped with S-NAP and MANAP in different proportions, and the results also follow this special rule of host-guest RTP systems. Furthermore, the phosphorescence intensity of the KPF-MANAP doped system is much higher than that of the KPF-S-NAP doped system. The drug trace impurity detection spectroscopic method proposed in this invention, utilizing a host-guest doping room-temperature phosphorescence strategy, involves doping naproxen with the host substance ketoprofen (KPF) through melting or grinding. By adjusting the doping ratio of KPF, it is ensured that KPF can only successfully construct an RTP system with trace impurities, while the abundant naproxen in the system cannot successfully construct an RTP system with the host substance ketoprofen, thus exhibiting a phosphorescence-silent state. Moreover, KPF has a specific response to specific impurity I; the presence of other impurities that may be introduced or generated during naproxen synthesis does not interfere with the detection of the phosphorescence intensity of specific impurity I. This invention also systematically optimizes the detection method. By introducing the main component ketoprofen as a melt dopant into the active pharmaceutical ingredient (API), the content of specific impurity I can be quantitatively detected by spectral analysis, with a detection limit as low as 0.05%, achieving a breakthrough in the rapid quantitative detection of impurity I in naproxen API. In the process analysis of naproxen formulations, the main component ketoprofen can be added during the production of naproxen granules and tablets for grinding, and the changes in phosphorescence can be observed, enabling visualized impurity limit checks. It is applicable to dynamic impurity monitoring in the production process of naproxen API and formulations, offering advantages such as ease of operation, rapid response, and high sensitivity. In summary, this invention, through a specific detection mechanism that eliminates chromatographic separation and combines the visualization characteristics of phosphorescence signals, significantly simplifies the operational process and supports rapid on-site screening, demonstrating significant application potential in the field of pharmaceutical process analysis (PAT). Attached Figure Description

[0020] Figure 1 The following are the fusion doping spectra of KPF with MANAP and S-NAP in a proportional ratio according to the present invention (where the horizontal axis is wavelength (nm), the vertical axis is phosphorescence emission intensity (au), and the inset is a fluorescence and phosphorescence photograph; unless otherwise specified, the phosphorescence spectra used for phosphorescence spectral characterization and intensity statistical examination were all measured by a Hitachi 7100 fluorescence spectrometer).

[0021] Figure 2Phosphorescence evaluation of KPF molten doping with S-NAP and MANAP according to the present invention (wherein, a) phosphorescence photographs of KPF molten doping with S-NAP and MANAP respectively; b) comparison of phosphorescence intensity of KPF molten doping with S-NAP and MANAP at different ratios; c) phosphorescence spectra of KPF molten doping with S-NAP and MANAP at the optimal ratio (this standard spectrum was measured using an FLS1000 steady-state transient fluorescence spectrometer); d) phosphorescence lifetime and quantum yield of KPF molten doping with MANAP at the optimal ratio; e) phosphorescence lifetime and quantum yield of KPF molten doping with S-NAP at the optimal ratio).

[0022] Figure 3 Phosphorescence evaluation of KPF with S-NAP and MANAP after grinding and doping according to the present invention (wherein, a) phosphorescence photographs of KPF with S-NAP and MANAP after grinding and doping respectively; b) phosphorescence spectra of KPF with S-NAP and MANAP at the optimal ratio after grinding and doping respectively (this standard spectrum was measured using an FLS 1000 steady-state transient fluorescence spectrometer); c) comparison of phosphorescence intensity of KPF with different ratios of S-NAP and MANAP after grinding and doping respectively; d) phosphorescence lifetime and quantum yield of KPF with MANAP at the optimal ratio after grinding and doping; e) phosphorescence lifetime and quantum yield of KPF with S-NAP at the optimal ratio after grinding and doping).

[0023] Figure 4 This invention investigates the phosphorescence intensity of the ternary molten doping system and the specific response of KPF to MANAP (wherein, a) the relationship between the molten phosphorescence intensity ratios of different proportions of KPF and the three-component system with 0.1% impurity and the two-component system without impurities; b) the relationship between the content of different impurity I and the phosphorescence intensity ratio; c) fluorescence and phosphorescence images of molten doping with different MANAP contents; d) the selectivity of other possible impurities in the S-NAP production process compared with MANAP; and e) the anti-interference test of other possible impurities in the S-NAP production process compared with MANAP).

[0024] Figure 5 The phosphorescence intensity of the ternary grinding and doping system of this invention was investigated (wherein, a) the relationship between the phosphorescence intensity ratio of different proportions of KPF and the three-component system with 0.1% impurity and the two-component system without impurity; b) the relationship between different MANAP contents and the phosphorescence intensity ratio; c) fluorescence and phosphorescence images of grinding and doping systems with different MANAP contents).

[0025] Figure 6 Other impurities that may be introduced or generated during the S-NAP production process of this invention;

[0026] Figure 7The present invention provides an inspection method for testing the limits of impurities during the formulation process (wherein, a) the production process of S-NAP tablets and granules; b) phosphorescence spectra of S-NAP granules for testing the limits of impurities; c) phosphorescence photographs of S-NAP granules with different impurity contents; d) phosphorescence spectra of S-NAP tablets for testing the limits of impurities; e) phosphorescence photographs of S-NAP tablets with different impurity contents).

[0027] Figure 8 This is a summary of the principle and application examples of the naproxen special impurity I detection method of the present invention. Detailed Implementation

[0028] The present invention will be described in detail below with reference to embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of application of the present invention. The present invention is not limited to the following embodiments or examples. Any modifications and variations made without departing from the spirit of the present invention should be included within the scope of the present invention. Unless otherwise specified, the experimental materials or reagents used in the following embodiments are commercially available.

[0029] The present invention will be further illustrated below through embodiments, the purpose of which is solely to provide a better understanding of the invention. In a preferred embodiment of the present invention: the excitation light source is selected to have a light intensity of 400 mW / cm². 2 A 365 nm ultraviolet light source.

[0030] Example 1: Phosphorescence intensity of two-component doped binary systems with different mass ratios

[0031] 1.1 Methods

[0032] The two-component doping methods were: ketoprofen (KPF) and 6-methoxy-2-acetylnaphthalene (MANAP) doping (hereinafter referred to as KPF:MANAP); and ketoprofen (KPF) and naproxen (S-NAP) doping (hereinafter referred to as KPF:S-NAP). KPF, MANAP, and S-NAP raw materials were all commercially available, with a purity greater than 99%. The S-NAP raw material underwent further purification via column chromatography and recrystallization to obtain high-purity S-NAP before being used in subsequent experiments.

[0033] The different mass ratios of KPF to MANAP or S-NAP in the binary components are 1:10, 1:5, 1:1, 10:1, 100:1, 200:1, and 500:1.

[0034] Doping methods: Melt doping involves heating the mixture with a hot air gun to melt and mix it evenly, then allowing it to cool and solidify naturally; Grinding doping involves grinding the mixture thoroughly with an agate mortar until it is evenly mixed.

[0035] Excitation source: Illumination intensity of 400 mW / cm 2A 365 nm ultraviolet light source.

[0036] 1.2 Results

[0037] Under 365 nm ultraviolet light excitation, the molten binary system exhibited yellow-green phosphorescence emission centered at 540 nm. Figure 1 , Figure 2 The fusion doping spectra of KPF with MANAP and S-NAP in direct and inverse proportions are shown below. Figure 1 As shown, under 365 nm UV excitation, KPF exhibits phosphorescence when doped with S-NAP and MANAP at a ratio of 100:1, with the phosphorescence intensity with MANAP being significantly stronger than that with S-NAP; no phosphorescence emission is observed when doped at a ratio of 1:100. Phosphorescence diagrams of KPF molten-doped with MANAP and S-NAP at different mass ratios are presented. Figure 2 a) and phosphorescence intensity at 540 nm ( Figure 2 As shown in b), different doping ratios result in different phosphorescence intensities. When the doping ratio is greater than 1:5, the phosphorescence intensity of KPF:MANAP is significantly higher than that of KPF:S-NAP. The optimal doping ratio is 200:1, at which point both KPF:MANAP and KPF:S-NAP exhibit the highest phosphorescence intensities, and the difference in phosphorescence intensity between KPF:MANAP and KPF:S-NAP is the largest. The phosphorescence spectrum at the optimal melt doping ratio (200:1) is shown below. Figure 2 As shown in c, the intensity of KPF:MANAP is significantly higher than that of KPF:S-NAP; time-resolved spectrum ( Figure 2 d and Figure 2 e) Analysis showed that KPF:MANAP exhibited an ultralong lifetime (>100 ms), and its phosphorescence lifetime was approximately 4 times that of KPF:S-NAP; quantum yield results indicated that the molten KPF and MANAP system ( (1.21%) has excellent phosphorescence properties.

[0038] Under 365 nm ultraviolet light excitation, the polished binary system still emits yellow-green phosphorescence centered at 540 nm. Figure 3 Phosphorescence patterns and intensities of KPF ground and doped with MANAP and S-NAP at different mass ratios are shown below. Figure 3 a) and Figure 3 As shown in b), different doping ratios result in different phosphorescence intensities. When the doping ratio is greater than 1:1, the phosphorescence of KPF:MANAP is significantly stronger than that of KPF:S-NAP. The optimal doping ratio for KPF:MANAP is 200:1, and the optimal doping ratio for KPF:S-NAP is 10:1, at which point the phosphorescence intensity is the highest. The phosphorescence spectra under the optimal grinding and doping ratios (KPF:MANAP=200:1 and KPF:S-NAP=10:1) are shown below. Figure 3 As shown in c, the intensity of KPF:MANAP is significantly higher than that of KPF:S-NAP; time-resolved spectrum ( Figure 3 d and Figure 3 e) Analysis shows that grinding doping can significantly improve the phosphorescence lifetime of KPF:MANAP, which is about 9 times longer than that of KPF:S-NAP; quantum yield results also show that KPF:MANAP has superior phosphorescence performance compared to KPF:S-NAP.

[0039] Example 2: Phosphorescence Intensity Examination of a Ternary Doped System

[0040] To further explore the application potential of KPF in S-NAP impurity testing, a ternary molten doping system was set up according to the impurity limit of 0.1% for S-NAP specified in the pharmacopoeia. Different mass ratios of host KPF were introduced under the condition that S-NAP:MANAP = 1000:1. The ratio of the phosphorescence intensity value I1 at 540 nm to the background phosphorescence intensity I0 without impurities (i.e., I1 / I0) was observed. The optimal doping ratio of KPF:S-NAP:MANAP was determined to be 200:1000:1. Figure 4 a) At this point, the I1 / I0 value is the highest. Fluorescence and phosphorescence patterns of molten doping with different MANAP contents (KPF:S-NAP:MANAP = 200:1000:0 ~ 32, MANAP impurity content is 0% ~ 3.2%) are shown in the figure. Figure 4 As shown in Figure c, the phosphorescence intensity gradually increases with the increase of MANAP impurity content. To investigate the applicability and quantitative range of this method for detecting MANAP impurities in S-NAP, the optimized KPF:S-NAP doping ratio was fixed at 1:5, and a graph was plotted showing the relationship between the phosphorescence intensity ratio (I1 / I0) and the lg value of impurity content percentage multiplied by 100 (i.e., lg(content of special impurity I × 100)). Figure 4 As shown in b, within the MANAP content range of 0.05 ~ 3.2%, I1 / I0 exhibits a good linear relationship with the lg value of impurity content multiplied by 100, yielding the linear equation y = 0.5072x + 2.8156, with a correlation coefficient R. 2 With a value of 0.9945, it is possible to quantitatively detect the impurity MANAP in S-NAP raw materials.

[0041] The results of grinding and doping are as follows Figure 5 As shown, similarly, the optimal doping ratio of KPF:S-NAP:MANAP is 200:1000:1 ( Figure 5 a); As the content of the impurity MANAP increases, the phosphorescence intensity also increases ( Figure 5 c), the relationship between I1 / I0 and impurity content multiplied by 100 is as follows: Figure 5As shown in b.

[0042] Example 3: KPF's specific response to MANAP

[0043] To verify the specific response of KPF to MANAP, this invention determined other impurities that may be introduced during the synthesis and production of naproxen. Figure 6 Commercially available, all with a purity greater than 98%. Observe the phosphorescence spectral changes of KPF after molten doping with MANAP and other impurities, such as... Figure 4 As shown in Figure d, compared with other impurities, the addition of MANAP to KPF significantly changes the phosphorescence intensity, indicating that KPF has good selectivity for MANAP. Furthermore, the results of the anti-interference experiment (doped with KPF, MANAP, and another impurity) are as follows: Figure 4 As shown in Figure e, the phosphorescence intensity of the horizontal axis 2-10 (doped with KPF, MANAP, and another impurity) is not significantly different from that of the horizontal axis 1 (doped with KPF and MANAP), indicating that the selective response of KPF to MANAP is not affected by the addition of other impurities, further confirming the excellent RTP response of KPF for impurity inspection in S-NAP.

[0044] Example 4: Accuracy Examination of the Inspection Method

[0045] To systematically evaluate the reliability of the host-guest doping room temperature phosphorescence method established in this invention for the quantitative detection of impurities in S-NAP active pharmaceutical ingredients, a comparative study was conducted using the standard high-performance liquid chromatography (HPLC) method specified in General Chapter 0512 of the 2020 edition of the Chinese Pharmacopoeia. The experimental design included spiked recovery tests at three concentration gradients: low (0.1%), medium (1%), and high (2%), as shown in Table 1. The average recovery rates at each concentration level met the requirements of the quantitative analysis method. Paired-samples t-tests (95% confidence interval) were performed on the two sets of detection data using IBM SPSS Statistics 26 software. The statistical results showed P=0.471>0.05, indicating no statistically significant difference between the results obtained by the two analytical methods. This finding confirms that the spectroscopic method established in this invention has accuracy comparable to current legal methods in the quantitative detection of impurities.

[0046] The experimental results are shown in Table 1.

[0047] Table 1. Comparison of spiked recoveries of different impurity contents in this experimental system with those of the naproxen impurity test method specified in the pharmacopoeia by HPLC.

[0048]

[0049] Example 5: Inspection method used for impurity limit testing during formulation process.

[0050] To expand the application of this invention in quality control during naproxen formulation production, representative tablet and granule model formulations were constructed based on formulation design principles. Key process validation showed that adding the main compound KPF during the granulation stage or after tableting followed by grinding (KFP:S-NAP = 1:5) enables room-temperature phosphorescence visualization detection of impurities as low as 0.1% in the formulation. Figure 7 As shown, it can monitor the dynamic changes of impurities in the production process of different dosage forms in real time.

[0051] In summary, this invention provides a method for detecting specific impurity I in naproxen based on host-guest doping and room-temperature phosphorescence, using ketoprofen as the host material and naproxen specific impurity I as the guest material. This method can achieve qualitative or quantitative analysis of specific impurity I in naproxen. The principle and application of this invention are as follows: Figure 8 As shown in the example, the phosphorescence intensity of the ketoprofen doped with specific impurity I is much higher than that of the ketoprofen doped with naproxen. When the mass ratio of ketoprofen, naproxen, and specific impurity I is 200:1000:1, ketoprofen and specific impurity I produce a bright RTP, while naproxen does not interfere, thus enabling the detection of specific impurity I in naproxen. The host-guest doping room-temperature phosphorescence strategy developed in this study overcomes the dependence of traditional drug impurity detection methods on complex pretreatment equipment and specialized operators. Its detection sensitivity (LOD=0.1%) meets the pharmacopoeia limit for specific impurity I and has the following technical advantages: 1) Specific detection can be achieved without chromatographic separation; 2) The detection time is shortened from 45 min in conventional HPLC to 10 min; 3) Visualization characteristics support rapid on-site screening. These features make it demonstrate significant application value in the field of pharmaceutical process analysis (PAT).

[0052] It is worth noting that the above description is only a preferred embodiment of the present invention. It should be pointed out that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A ternary doped system, characterized in that, The doping includes ketoprofen, naproxen and special impurity I, and the special impurity I is 6-methoxy-2-acetylnaphthalene.

2. The system of claim 1, wherein, The mass ratio of ketoprofen to naproxen is 1:

5.

3. The system of claim 2, wherein, The mass ratio of ketoprofen, naproxen and special impurity I is 200:1000:0~32.

4. The system of claim 3, wherein, The mass ratio of ketoprofen, naproxen and special impurity I is 200:1000:

1.

5. A method for checking a specific impurity I in naproxen based on host-guest doping room temperature phosphor, characterized in that, The doping system is obtained by mixing ketoprofen as a host material and special impurity I of naproxen as a guest material, and the special impurity I is 6-methoxy-2-acetylnaphthalene, and then the room temperature phosphorescence signal under 365 nm ultraviolet light excitation is detected to realize qualitative or quantitative analysis of the special impurity I in naproxen.

6. The method of claim 5, wherein, The amount of ketoprofen is between naproxen and special impurity I.

7. The method of claim 6, wherein, The mass ratio of ketoprofen to naproxen is 1:

5.

8. The method of claim 7, wherein, The content of the special impurity I in naproxen is obtained by a linear equation y=0.5072x+2.8156, wherein x is the logarithmic value of the content of the special impurity I multiplied by 100, that is, lg (the content of the special impurity I multiplied by 100), the range of x is 0.05~3.2, y is the ratio of the phosphorescence intensity under 365 nm ultraviolet light excitation of the molten doping system I1 / I0, I1 is the phosphorescence intensity of the doping system, and I0 is the background phosphorescence intensity without the special impurity I.

9. Use of the method according to any one of claims 6 to 8 for the dynamic monitoring of impurities in the production of naproxen formulations, characterized in that, The special impurity I content is monitored in real time by the change of phosphorescence intensity through adding ketoprofen grinding after the granulation or tabletting process in the tablet or granule production process.

10. Use according to claim 9, wherein: The visual detection limit of the special impurity I in the preparation is 0.1%, and the on-site rapid screening is realized by visual phosphorescence signal change.

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