Research Of Critical Quality Attribute Of Croscarmellose Sodium In Domperidone Tablets

Pharmaceutical excipients are traditionally considered pharmacologically inert ingredients in formulations,but in practice the quality of pharmaceutical excipients has a crucial impact on the safety,efficacy,and stability of drugs.Formulation carriers to achieve functionality are pharmaceutical excipients and the study of critical quality attributes of excipients should accompany the whole process of formulation development and production,and have a certain guiding role in the quality control of the formulation.Based on the above reasons,it is necessary to pay attention to the effect of pharmaceutical excipients on the quality of formulations,and to clarify the critical quality attributes of pharmaceutical excipients in order to provide a basis for improving the consistency of the quality of excipients and the products of formulations.In this study,disintegrant croscarmellose sodium（CCS）was used as the research object,domperidone of the BCSⅡclass were used as the model drug to investigate the effects of CCS from different sources on the disintegration time and in vitro dissolution of domperidone tablets.The critical quality attributes were clarified with the orthogonal partial least squares（OPLS）and spearman correlation analysis,and elucidate the influence of excipient properties on formulation quality.1 Study on critical material attributes of CCS from Different SourcesPhysical fingerprinting and similarity evaluation were applied to calculate the similarity between samples and to evaluate the compressibility of CCS.From the physical fingerprinting,it can be observed that there are differences in the physical indexes of CCS from different sources,with the greatest differences in swelling,settling volume and loss on drying;the compressibility evaluation showed that the compressibility of the samples from manufacturer E was poor.Principal component analysis was used to evaluate the fluidity of the samples,and two out components were extracted to finally obtain the ranking of the fluidity of the samples.Clustering analysis of different sources of CCS revealed that all samples could be classified into three categories,further demonstrating the differences in quality of CCS from different sources.The heat map was used to show the correlation between the physical indicators.2 Correlation analysis between water absorption properties and structure of CCS from different sourcesThe water absorption properties and structural differences of CCS were analyzed,and the association between them was also examined.The water uptake rate and the moisture sorption isotherms of CCS were determined by dynamic water vapor sorption,and the model was fitted to the moisture sorption isotherms.The results indicated that there were differences in water uptake rate and water uptake of CCS from different sources;the model fit results showed that the GAB model was the best fit model,and the monolayer moisture content of CCS from different sources was different.The IR spectra of the samples were collected,and the results showed that the IR spectra of CCS from different sources differed at 1745 cm^-1 due to the differences in substituents and cross-linked structures.The pharmacopoeia methods were used to determine the degree of substitution,low field NMR technique was used to determine the crosslink density,combined with the results of infrared spectrogram and moisture sorption isotherm fitting,it was found that CCS from different sources have some differences in structure and that the degree of basic substitution has a positive effect on the water absorption properties.Using NIR spectroscopy,MSC+2std+Norris smoothing was selected as the pretreatment method to establish a robust and well predictive model for rapid analysis of the degree of substitution.3 Study on the critical quality attributes of CCS in domperidone tabletsThe prescriptions were screened by single factor test and domperidone tablets were prepared by direct tableting of powder.The differences in disintegration time and dissolution between domperidone tablets prepared by CCS from different sources were compared.Domperidone tablets were prepared with the best prescription,and the tablet quality examination all conformed to the requirements,but the disintegration time of domperidone tablets prepared by CCS from different sources differed greatly,indicating that the disintegration properties of CCS from different manufacturers differed significantly.The critical quality attributes of CCS in domperidone tablets were determined.The OPLS model and Spearman correlation analysis were used to identify the critical quality attributes of CCS in domperidone tablets,using the indicators of CCS as independent variables and the disintegration time and in vitro dissolution of domperidone tablets as dependent variables.Combining the two methods,acidic substitution,basic substitution,tapped density,m₀,bulk density,span,and inter-particle porosity of CCS were identified as the critical quality attributes affecting disintegration time;swelling,acidic substitution,settling volume,loss on drying,D₉₀,span,and D₅₀ were the critical quality attributes affecting in vitro dissolution.Using multiple linear regression,the mathematical models of tablet disintegration time and in vitro dissolution were established:Y₁=-224.481×S-68.146×Ie+244.577 and Y₂=-0.427×Sw-0.028×D₉₀+98.260.The results indicated that it was feasible to evaluate the quality differences of the excipients using physical fingerprinting,principal component analysis as well as indicator correlation visualization.The critical quality attributes of CCS were identified by correlating the indicators of CCS with the disintegration time and in vitro dissolution of the model tablets to provide some reference basis for the subsequent excipient manufacturers to control the quality of excipients.