Research On The Spatial Coupling Effect Of Serial Chinese Medicine Pharmaceutical Process Design

The establishment of design space is one of the core steps of application quality from Quality by Design.Raw material specifications are established in order to ensure that the materials coming into a process are of acceptable quality.The tight relationship between the incoming materials,the process,and the product end quality is recognized in the ICH Q8 document as areas to be considered in the development of a design space.Any part of the process is disturbed In the process,the quality variation of intermediate products will be transferred to the final product with the pharmaceutical process,resulting in the difference of product quality between batches.In this paper,Panax Notoginseng Saponins(PNS)tablets were used as the carrier and combined with chemometrics methods to investigate the relationship between the spray drying conditions,the physical and chemical quality properties of the raw materials and the dissolution properties of the PNS tablets.The multiple latent variable design space and the spray drying process design space of the raw material were established.The coupling effect of the design space of the raw material and the process design space was discussed,and two control strategies were provided for the intermediate of the two links.The main contents are as follows:1.The establishment of the design space for pressing processThe quality attributes of raw materials and excipients of oral solid preparations are closely related to the quality of final products.In the first part of this paper,the effects of the physical and chemical properties of the raw powder and the auxiliary powder on the dissolution properties of the PNS gel skeleton were investigated,and the design space of the key quality properties of the powder was established.The relationship model of Physicochemical Quality Properties of raw materials,excipients and prescriptions and dissolution properties of tablets was established by PLS modeling method,and the effects of physical and chemical properties of raw materials and excipients on the dissolution properties of tablets were deeply understood.The dry weight loss,hygroscopicity,specific surface area,particle size distribution width of the PNS material and the size distribution width of HPMC K4M,D10,dry weight loss,D90,cohesive force index,hygroscopicity,pine density and vibratory density are the key material properties that affect the dissolution of PNS gel skeleton.On the basis of defining the key material properties that affect the dissolution properties of the tablets,the new observation data are obtained by Monte Carlo method,and the quality design space of the raw materials,auxiliary materials and prescriptions is set up according to the dissolving target of the tablets.The quality control targets of the raw materials,auxiliary materials and prescriptions were made clear.The quality control of materials in latent variable space was considered.2.The establishment of design space for spray drying processThe key process parameters were determined by Plackett-Burmann experimental design,which were the concentration of material liquid,the atomization pressure and the air inlet temperature.The Box-Behnken experimental design was used to quantify the relationship between the key technological parameters of spray drying and the quality properties of the spray dry powder and the dissolution performance of the tablets.The physical quality properties and the quality properties of the tablet powder,which were affected by the spray drying conditions,include the loose density,the vibratory density,the particle size,the particle size distribution width and the intergranular space.The porosity,cohesive force index,specific surface area,dry weightlessness and hygroscopicity,and cumulative release and cumulative release RSD values of 2,4 and 6 hours were obtained.By predefining the target,the spray drying process design space that meets 4 targets at the same time is set up,and the confidence level of the confidence level alpha=0.05 is added to the design space.Design space is the core part of quality from the design concept.The establishment of design space is conducive to enhancing the understanding of spray drying process.According to the improvement of the understanding of the process,we constantly improve the process design space,so as to ensure the robustness of the process and the consistency of product quality..3.Study on the spatial coupling effect of series process designAccording to the Monte Carlo method,the data samples were simulated in the design space and the experimental space of the spray drying process.The quality attribute data of the spray dry powder was obtained by the polynomial model of the spray drying technology-the quality attribute of the spray dry powder.The quality attribute of the spray dry powder was projected through the PLS model to the quality design space of the raw material,and through the the MBPLS model was projected to the prescription quality design space.The results show that most of the sample points within the design space of the spray drying process fall into the space of material quality design space and the design space of the prescription quality.In the experimental space,1052 sample points have not fallen into the material quality design space,and 100 samples are not falling into the prescription quality after the random collocation of the existing batch.In the design space,the 100 unqualified samples are mixed with other batch materials,and their quality attributes can also fall into the prescription quality design space.The results show that the quality attribute of the sample point is not falling into the quality design space of the raw material,and the quality attribute of the mixed powder with the auxiliary materials falls into the prescription design space,and the results of the dissolution experiment are full of requirements,and the process design space is confirmed.The coupling effect of quality space and prescription quality design space exists.This subject provide two control strategies for the quality of intermediates in two processes.First,the material is controlled by the variable quality control limit of the quality attribute latent variable design space.Secondly,according to the coupling effect of the design space between the processes,the relationship between the quality of the process intermediate and the final product is understood deeply,and the raw materials are taken by the raw materials.To further break through the quality control limit,expand the application range of materials,control the quality of the mixture of raw materials,so as to enhance the flexibility and degree of freedom in the process control.To improve the overall quality control from the original variable space to the latent variable space,from a process unit to multiple process units.It provides new ideas for quality design and process design of Chinese medicine preparations.