Application Of Room Temperature Phosphorescence And Free Radical Luminescence Of Trace Guest In Impurity Limit Test And Crystal Analysis Of Substance

Any substance that affects the purity of the drug is called impurities,including organic impurities,inorganic impurities,residual solvents,as well as enantiomeric impurities and drug polymorphs,which are receiving increasing attention.Drug impurities often have no therapeutic effect and can affect the stability and efficacy of drugs,thus impurity research will be directly related to drug quality and clinical drug safety.The primary task of impurity research is to find a sensitive and specific analytical method to accurately distinguish and determine the type and content of drug impurities,and finally control them within a safe and reasonable limit.Since various methods have certain limitations,different analytical methods are needed to complement and validate each other in the actual drug impurity examination and crystal form analysis.The typical spectroscopic methods of absorption,scattering and fluorescence are simple and sensitive,but in the practical application of drug quality control,they are susceptible to the interference of excipients and the drug body itself,which has a great impact on the accuracy and specificity of the analysis.Therefore,it is important to develop new spectral analysis methods.The host-guest doped room temperature phosphorescence and two-component photo-induced radical luminescence originate from the presence of trace amounts of guest substances in the system,and the structural composition of both luminescence systems is highly compatible with drug/impurities.Since a low doping ratio of the guest molecule results in a strong optical signal,the theoretical feasibility of applying these two methods to drug impurity studies is demonstrated.Long-life room temperature phosphorescence effectively overcomes the problem of fluorescence interference from excipients,etc.,and can improve the analytical accuracy and specificity.In addition,the ability of the molecular stacking form to modulate the phosphorescence emission makes it promising to be used for the indication of substance crystallographic characteristics,giving in situ and visualized analytical signals.In summary,the application of these two novel spectroscopic analysis methods in pharmaceutical quality control is well worth exploring.Based on this,this paper focuses on the application of room temperature phosphorescence and free radical luminescence in the analysis of drug impurities and crystal form of substances.The main contents are as follows:(1)Study on the mechanism of molecular thermal motion modulated room temperature phosphorescence and its application exploration in drug impurity warning.The host-guest doped room temperature phosphorescence emission relies on the interaction between the host and guest molecules at close distances,and thus the modulation of the host-guest distance and interaction is expected to be an effective modulator of RTP emission.Inspired by chromatographic separation,a general strategy to confer thermal response properties to the flourishing host-guest RTP materials was developed by cleverly using molecular thermal motion as a driving force to obtain temperature-sensitive phosphorescence materials by fully mixing the host-guest RTP materials with common column chromatography silica gel.Mechanistic studies show that the phosphorescence elimination originates from the separation effect of silica gel on the host and guest molecules,while the temperature response range mainly depends on the melting point of the organic host,reflecting the importance of molecular thermal motion in the process from the side.Based on this strategy,RTP materials with a wide range of temperature response can be obtained and used for multi-level information encryption and cold chain breakage monitoring.Furthermore,we used the molecular thermal motion modulated RTP emission strategy for the reporting of trace impurities in drugs.The advantage is not available for single-component RTP emission systems,and experimental results show that the three-component system is equally applicable.The extremely low doping concentration requirement of the guest molecule in the host-guest doped RTP system makes this method show good applicability and application prospects for trace impurity warning in APIs.(2)In-situ monitoring of crystal phase transitions by means of room temperature phosphorescence emission from a trace guest.In single-molecule RTP systems,the RTP emission properties of a substance depend mainly on the form and extent of its own molecular stacking.However,in the host-guest doped system,the guest molecule provides the luminescence signal as a trace impurity component,while the stacking form of the host molecule may affect the state of the guest molecule and thus modulate its luminescence.Here,we found that subtle differences in the stacking form of the host molecule triphenylphosphine can lead to differences in the phosphorescence emission of the guest molecule tetraphenylbenzidine,and thus the differences in the stacking state of the host molecule can be analyzed by the "optical signal" of the trace guest phosphorescence emission.In the process of triphenylphosphine crystal transformation,the change of phosphorescence emission wavelength of the doped system can be observed,so that the change of RTP emission color can reveal the phase transformation process of the host crystalline form.A spectroscopic analysis method using room temperature phosphorescence of the host and guest for substance crystallographic analysis was successfully established,which has the advantages of realtime,in situ and visualization compared with the conventional crystallographic analysis methods.The strategy is expected to show promising applications in the multi-crystalline characterization and quality control of drugs.(3)Application of photo-induced radical luminescence in drug impurity test and optical purity analysis.Under UV light irradiation,many organic molecules have the potential to generate radicals,but because of their instability,they need to be discovered and studied with the help of stabilizing effects of specific host substrates.Inspired by the host-guest doping strategy to construct room temperature phosphorescence materials,it is expected to enable rapid visual test and spectroscopic analysis of impurities through photo-induced luminescence of guest impurity radicals by exploiting the unique interactions between the drug host and the impurity guest.The relevant substance of the pharmacopoeia-listed NSAID analgesic S-naproxen is impurity I,i.e.6-methoxy-2-naphthone,with a limit of 0.1%.The simple doping of S-naproxen with impurity I produces a specific red luminescence under UV irradiation for a few seconds,and this red luminescence is clearly visible at the impurity limit level.Electron paramagnetic resonance characterization confirmed that the corresponding radicals were generated during the luminescence.Unlike the single conformation of S and R,the naproxen racemates did not show any significant luminescence upon irradiation with impurity I.Moreover,when 30% and more isomers are present in the S or R configuration of naproxen,there will be no photoluminescence of radicals,which can be attributed to the Wallach’s rule of stronger affinity interaction between isomers.The results of the series of analog doping experiments show that the system has good specificity.This work establishes a new method for spectroscopic analysis of drug impurity limit test and optical purity analysis of chiral drugs by using the unique luminescence form of radical luminescence.In summary,this thesis develops a new method for the spectroscopic analysis of drug impurity limits test and crystal form identification based on host and guest doped room temperature phosphorescence and free radical luminescence.