| The tablet is one of the commonly used dosage forms as for the stable physical and chemical properties and then convenient for storage,transportation,carrying and taking.The production process of the tablets can be divided into four types,namely direct compression,dry granulation,wet granulation and others according to the materials.The direct compression only involves mixing and tableting,which has the advantages of low production cost,high efficiency and high degree of continuity.With the advancement of production technology and the improvement of the understanding of the nature of materials,the use of more efficient and economical processing methods to produce traditional Chinese medicine(TCM)tablets is an urgent need of Chinese medicine manufacturers.Direct compression requires high fluidity and compressibility of the powder material,and the tableting process involves various mechanisms such as particle rearrangement,elastic deformation,plastic deformation,crushing,recombination,etc.,and proper formulation design and process design method are required.How to evaluate whether TCM powder is suitable for direct compression,how to select suitable excipients to correct the powder properties of TCM to meet the conditions of direct compression,is a key issue to be solved urgently for the direct compression of TCM.Under the guidance of QbD,this thesis studied the formulation design methodology of direct compression for TCM.The thesis selected representative TCM powder to establish a standard operating procedure of physical fingerprinting and compression behavior classification system,and evaluated the compressibility of TCM powder.Based on the physical property index and compression parameters,the critical quality attributes prediction model of TCM direct tablet was constructed.Then,the multi-objective design space was built and used to realize the characterization of the material properties,compression parameters and multi-dimensional interaction knowledge of the direct compression tablet.The iTCM intelligent Chinese medicine database was constructed.Based on the mechanism model,statistical model and intelligent optimization algorithm,the intelligent formulation design method of TCM direct compression tablet was established to improve the screening efficiency and reliability of excipients.The specific study contents included the followingfour parts:1.Collection,analysis and management of standard data of raw materials and excipients powdersIn order to ensure the accurate,reliable and tidy data of the physical properties of the raw materials and excipients,this section selected 19 physical indicators and established the standard operating procedures for the analysis of the physical properties of the powder.The iTCM database was designed and developed independently and 130 batches materials were collected and stored.Through the exploratory data analysis methods such as heat map analysis and principal component analysis,it was proved that the samples in the database were representative and had a wide range of physical properties.Principal component analysis showed that the TCM in the potential variable space can be classified according to roots,stems,leaves,flowers,fruits,seeds,etc.,and the excipients can be classified according to diluents,disintegrants,lubricants,etc.The average hygroscopicity of TCM powder was more than 23%.According to the classification of hygroscopicity in Chinese Pharmacopoeia,the TCM could be owned to the highly hygroscopic.The moisture content was about 5%,which meets the requirements of Chinese Pharmacopoeia.The particle size was small and the average values of D10,D50,D90 were 5.04?m,19.93 ?m and 55.50 ?m,respectively.Except that the Wumei extract powder can flow freely from the funnel,other TCM extract powders cannot flow freely.This phenomenon indicated that improving flowability was the critical factors for the direct compression of TCM powder.The TCM employed good compressibility and the average cohesion index was 153.85 N.Therefore,this part laid the data foundation for the subsequent development of intelligent formulation design methods.2.Evaluation of compression behavior of raw materials and excipients powdersPowder porosity and tensile strength vary with pressure.This part studied the compression behavior and regularity of TCM powder from the aspects of compressibility,compactability and tabletability.The Kawakita,Heckel,Shapiro and Gumham equations were chosen to describe the compressibility,ie the relationship between pressure and porosity.From these equations,six compression parameters,a,b-1,ab,Py,f and K,were extracted to describe whether the powder were rearranged,broken and plastic.The Ryshkewitch-Duckworth equation was chosen to describe the compactability,which was the relationship between pressure and tensile strength.And the bonding index kb was extracted to evaluate the bonding ability between particles during compression.The Power equation was established to describe the tabletability,which was the relationship between tensile strength and pressure.And the index d and g were extracted to classify the powder tabletability properties.The tabletability index g represented the shape of the tensile strength as a function of pressure.When g was equal to 1,the pressure was linear with the tensile strength;when g was greater than 1,the pressure and tensile strength were concave function;when g is less than 1,the pressure and tensile strength was a convex function relationship.The tabletability index d directly reflected the tensile strength of the materials under compressure.The materials can be divided into three types according to the d value,namely Type 1,Type 2 and Type 3,respectively.Type 2 can be further divided into three subtypes of Type 2A,Type 2B and Type 2C.Almost all TCM extracts belonged to Type 2.Type 2A powders had acceptable tabletability(TS>2.0 MPa)at low to middle pressure range(50?100 MPa),while having good tabletability(TS>3.0 MPa)at middle to high pressure range(100?150 MPa).Type 2B powders had acceptable tabletability only at middle to high pressure range(100?200 MPa).Type 2C powders did not produce tablets that meet the requirements over the entire pressure range.Therefore,according to the classification of compression behavior,it can provide reference for formulation design,and provide basic model support for the establishment of intelligent formulation design method.3.Establishing intelligent design method for direct compression formulation of TCM based on powder physical propertyIn order to realize the intelligent formulation design of TCM direct compression tablet,this part proposed and constructed the periodic table of TCM powder physical property.Optionally,two target properties were used as the horizontal axis and the vertical axis,and the materials were periodically arranged in the two-dimensional coordinate system.The physical periodic table had the positioning function and correction function.The positioning function of the periodic table reflected the powder characteristics on the horizontal axis and the vertical axis,and the powder needs to be corrected according to the positioning.The correction function was realized by the correction formula.According to the minimum requirement of the powder to satisfy the horizontal axis or the vertical axis,the initial excipients and its proportion were obtained through linear relationship.20 excipients were selected and the minimum proportions required were calculated.The initial proportions,combined with the mathematical model to get an accurate proportions,to improve the efficiency and reliability of TCM formulation design.In addition to the physical properties of the powder,the compression parameters were also a key part of implementing the intelligent formulation design.Based on the seven parameters of compressibility,compactability and tabletability,ie,a,b-1,ab,f,Py,kb and d,a compression behavior classification system(CBCS)was constructed.The classification system consisted of five steps to classify the powder and finally determine whether the powder was suitable for direct compression.The results showed that the classification system can classify the compression behavior of the materials tested and provide a basis for the screening of excipients in the formulation designBased on the material properties and compression parameters of the materials,the three PLS2 models and three potential design spaces were developed.The results showed that the R2 Ycum and Q2 Ycum models were 69.0%and 67.8%for the Model 1,and 69.3%and 68.1%for the Model 2,which indicating that the interpretation performance and prediction performance of the model were basically the same.The models R2 Ycum and Q2 Ycum were 73.7%and 72.4%for model 3 indicating that the model interpretation performance and prediction performance were slightly higher than the models established separately.In summary,different formulation design methods can be selected based on the acquired data.If there is powder physical property,the powder physical property periodic table can be selected to determine the suitable excipients and their proportions.If there is powder compression behavior equation,the suitable parameters can be selected by combining the compression parameters PLS2 model latent variable design space.If both the physical property parameters and the compression behavior data are available,the latent variable design space of the PLS2 model integrated by the two can be selected to screen suitable excipients.4.Verification of intelligent formulation design methodIn view of the above results,this part is verified by selecting four kinds of TCM extract powder and three excipients.The four TCM extract powders belong to the Type 2A in the compression behavior classification system.Among the three excipients,MCC belonged to Type 1,lactose belongs to the Type 2B and pregelatinized starch belonged to Type 2C.The results showed that the direct compression performance was significantly enhanced when Type 1 excipients were added to Type 2A samples.Adding Type 2B samples can improve the direct compression performance under medium and high pressures while adding Type 2C samples requireed high pressure to meet the direct compression performance.Therefore,Type 1 excipients are preferred for TCM extracts powder.This part of the verification results demonstrated that the compression behavior can quickly screen the excipients and determine the amount of excipients,and the formulation can be projected to the design space established in the previous section to further verify the reliability of the design space.Tianshu Tablet was selected as the research object,and the formulation design based on physical properties periodic table and design space was validated.The results showed that the two methods could select suitable excipients and meet the quality requirements of the tablet.It demonstrated that the intelligent formualtion design method established in this thesis has a certain guiding role in the formulation design.Therefore,this part showed that the intelligent design method of direct tableting prescription based on powder physical properties has a guiding role in formulation design.Based on the above four parts of research,this thesis constructed a complete intelligent formulation design method for direct compression tablet of TCM from the physical property collection to the method verification.Through the research in this thesis,it can provide reference for guiding the screening and dosage optimization of excipients in the formulation design,and provide a basis for the design of the direct compression process of TCM powder. |
PDF Full Text Request