| Hypertension as a common chronic disease,has a high prevalence rate and shows a trend of increasing year by year.The population is getting younger.Drugs to treat hypertension are in high demand.Nifedipine is an antihypertensive drug,occupies a large market share which was first developed and marketed by Bayer.From the initial sustained release tablet to the current controlled release tablet,the original research drug Adalat has the largest market share at present.Although there are a number of domestic manufacturers of generic nifedipine,only three enterprises have passed the consistency evaluation,and the efficacy is not satisfactory.Nifedipine is a light yellow crystalline powder.Which is a kind of two hydrogen pyridine class calcium ion blockers.In the trearment of hypertension which plays an important role by the way of a long-term mechanism.But it has a very high photosen-sitivity,under the light conditions will be oxidized to form impurities and lead to toxic side effects.In the production process,pharmaceutical excipients also can produce im-portant influence on stability of active pharmaceutical ingredients.This article takes the antihypertensive drug nifedipine as the research object.Ac-cording to the characteristics of nifedipine,the spectral technology is introduced to carry out the research from the three aspects of medical excip ients,raw materials and dissolution.This study provides a fast,nondestructive,green monitoring method and process analysis technology for the problems encountered in the drug research and anal-ysis and actual production of nifedipine,and provides technical support for improving drug consistency.Specific research contents are as follows:(1)Research and application of NIRS and Raman in the qualitative identification of pharmaceutical excipientsIn this study,combined with NIRS and Raman spectroscopy,three levels of dis-criminant analysis models were established for the discriminant analysis of pharmaceu-tical exciphants:1.Raman spectrogram analysis;2.Discriminant analysis method for spectral similarity of cosine of included angle;3.OPLS-DA discriminant analysis.It was found that Raman spectroscopy and NIRS have their advantages and disadvantages in the process of discriminant analysis of pharmaceutical excipients.For the samples with better Raman spectral absorption peak,rapid identification can be realized by the attribution of spectral signal peak.For the samples with serious baseline drift of Raman spectra,different stoichiometry methods were investigated to remove baseline drift,and a discriminant analysis model was established for the spectra after baseline correction.The results showed that the model established after baseline correction could realize the accurate discrimination of starch samples,but could not distinguish cellulose sam-ples.The original spectral characteristic absorption peak of NIRS is not obvious,which needs to be treated with stoichiometry.For the samples with poor Raman spectral qual-ity,NIR spectroscopy combined with stoichiometry can be used to establish a model,which can realize the accurate discrimination of samples.(2)NIRS used for the eutectic characterization of NFD·INA and online monitoring of its formation processEutectic technology can effectively solve the photosensitivity problem of nifedi-pine.In this study,NIRS was introduced to realize the feasibility study of NFD·INA characterization and online monitoring of drug eutectic formation process.Finally,NIRS combined with chemometrics was used to realize non-destructive and rapid mon-itoring of purity of NFD·INA.NFD·INA has the first-order frequency doubling absorp-tion peak of O-H hydrogen bond at 6696 cm-1,the first-order frequency doubling ab-sorption peak of O-H hydrogen bond at 5095 cm-1,and the first-order frequency dou-bling absorption peak of N-H hydrogen bond at 6476 cm-1.The feasibility of NFD·INA eutectic characterization was proved by establishing a quantitative model and charac-terization by conventional methods.NIRS is used for on-line monitoring of eutectic formation process.(3)The study of NIRS on dissolution behavior of controlled release tablets of nifedipineIn vitro dissolution is a key parameter reflecting the quality of sustained-release tablets.Most studies have measured the dissolution of tablets from a macroscopic point The purpose of this study was to explore the role of water in the dissolution process of nifedipine controlled-release tablets from a microscopic perspective,and to provide a new way to understand the dissolution behavior of nifedipine controlled-release tablets In this study,the dissolution solution was slowly added to the drug-containing layer,and the NIR spectra were collected according to the set time.The NIRS technology combined with aquaphotomics was used to analyze the changes of water with different structures in the dissolution process.The results show that the change of water structure is consistent with the dissolution process.In the hydration stage of the dissolution of the controlled release tablets,Sr combines with the semi-permeable membrane to form a channel firstly.After the formation of the channel,So,Si,S2 and S3 enter the drug layer and further combine with the booster layer.In the drug release stage,the drug is pushed out by the booster layer.This study not only deepens the understanding of the dissolution process of controlled-release tablets,but also opens up a new perspective for the analysis of molecular interaction in water system through the understanding of water interaction.The innovation points of this paper include(1)The advantages and disadvantages of NIRS and Raman spectroscopy in the qualitative discriminant analysis of pharmaceutical excipients were compared and stud-ied.This two technologies were comprehensively used to establish a composite spectral identification system,which improve the discriminant accuracy and save analysis time.Realized the accurate discriminant analysis of pharmaceutical excipients.(2)The feasibility study of NFD·INA characterization by NIRS is realized.As a fast and nondestructive characterization method,combined with the formation principle of eutectic,it can be popularized and applied in the characterization of eutectic of other drugs.(3)Through the online monitoring of drug eutectic formation process by NIRS,the visualization of the eutectic formation process and the effective judgment of the end point can be realized.(4)For the first time,NIRS and aquaphotomics were used to study the changes of water in the dissolution process of tablets from the microscopic point,which not only deep the understanding of the dissolution process of controlled-release tablets,but also opened up a new perspective for the analysis of molecular interaction in water system through the understanding of water interaction. |
