Research On Intelligent Design Method Of Dry Granulation And Tableting Prescription Of Traditional Chinese Medicin

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.Roll compaction/dry granulation(RCDG)is an important manufacturing route in the preparation of traditional Chinese medicine(TCM)tablets.The main advantages of RCDG are the absence of water or other solvents and cost-intensive drying steps,making this technique feasible for moisture-and heat-sensitive materials;moreover,RCDG is a relative simple manufacturing route in the pharmaceutical industry.The main drawbacks of RCDG are the formation in one take and the loss of tabletability.Guided by Quality by Design(QbD)concept,this thesis focused on the formulation design methodology of tableting by dry granulation for TCM.Representative materials were characterized by material properties and compression parameters.A model for predicting the quality attributes of tablets based on the physical properties and compression parameters of materials was established.The intelligent formulation design method of tableting by dry granulation for TCM was established to improve the screening efficiency and reliability of excipients.the specific study contents included the following three parts:1.Evaluation of properties of raw materials and excipients powdersThe compression behavior classification system(CBCS)parameters were used to characterize the compression properties of 45 batches of traditional Chinese medicine extract powder,which included 20 batches of spray dried powders and 25 batch of the belt dried powders.Meanwhile,combined with the CBCS parameters data of 67 batches of raw materials and excipients in the iTCM database,the CBCS parameters dataset of 112 batches of raw materials and excipients were established.Principal component analysis(PCA)was conducted on the above-mentioned CBCS parameters dataset.The results showed that excipients were mainly distributed in the left side of latent variable space,and TCM extract powders was mainly distributed in the right side of latent variable space.Namely the difference between excipients and TCM extract powders mainly come from the information contained in the first principal component,and the variables that have the greatest influence on the first principal component are the parameters f,1/b,g,K and a,which mainly characterize the compressibility,tabletability and fracturing tendency of materials in the compression process.In the latent variable space,the distribution of belt dried powders were concentrated in the middle position,while spray dried powders were widely distributed and contains belt dried powders,which indicated that the drying methods have a certain effect on the powder compression behaviors.NIR diffuse reflectance spectra of 112 batches of pharmaceutical powders were rapidly measured by a portable near infrared spectrometer,the NIR spectra dataset of raw materials and excipients were established.It was found that the NIR spectral data pretreated by SNV+SG+1D method has better classification performance than physical properties,and has better prediction performance for particle size parameters and hygroscopicity of materials.Adding NIR spectral data to the input of tablet quality prediction model of direct compression can improve the prediction performance of the model,and the combination of physical parameters and NIR spectra can more comprehensively characterize the properties of raw materials and excipients.2.Study on the influence of dry granulation process on the compression behaviors of granulesIn this paper,10 batches of materials(3 batches of excipients and 7 batches of TCM extract powders)were studied under different hydraulic pressure and two sieve fractions.The differences of compression behaviors between the original powders and two sieve fractions dry granulated granules prepared under different hydraulic pressure were explored.The effects of hydraulic pressure and sieve fraction on the compression behavior of granules,including compressibility,compactibility and tabletability were studied.The result showed that under the same material condition,the hydraulic pressure and sieve fractions were inversely proportional to the compressibility,compactibility and tabletability of the materials.Meanwhile,the differences of compression behaviors of 35 batches of representative materials(17 batches of TCM extract powder and 18 batches of excipients)and their dry granulated granules prepared under hydraulic pressure of 70 bar and 125-250 μm sieve fraction,and the relationship between the changes of tabletability and the changes of compactibility and compressibility of materials were studied.The results showed that after dry granulation,the tabletability of 11 batches of materials increased or basically unchanged,such as E62 low substituted hydroxypropyl cellulose.Z73 Atractylodis Rhizoma and Z84 Glycyrrhizae Radix et Rhizoma.There were 24 batches of materials with loss of tabletability,including 16 batches of excipients and 8 batches of TCM extract powders.Compared with the TCM extract powders,the excipients were more prone to loss of tabletability in the process of dry granulation.According to the compression curves of the raw materials and the corresponding dry granulated granules,the tensile strength and solid fraction of the tablet under the same compression force were extracted.The physical properties and the compression force data of the materials in the direct compression and tableting by dry granulation process were fused.Based on the same independent variable matrix,the tensile strength and solid fraction of the tablet were predicted,In the same potential variable space,the manufacturing properties space of materials in different process routes were visualized,and the process routes selection of tablet preparation based on the physical properties of powder was realized.3.Study on the formulation design method of tableting by dry granulation processThe critical quality attributes(CQAs)of tableting by dry granulation were defined as the tensile strength and solid fraction of tablet,and were used as the output variable of the model.PLS model 1 was established with compression forces and the materials physical properties as the input variables;PLS model 2 was established with compression forces,the materials physical properties and compression parameters as the input variables;PLS model 3 was established with compression forces and compression parameters of the intermediate granules as the input variables;PLS model 4 was established with compression forces,materials physical properties and compression parameters,compression parameters of the intermediate granules as the input variables.Results shown that the R2Ycum of model 1,2,3 and 4 was 67.3%,80.7%,77.3%and 84.0%respectively,and Q2cum was 67.0%,80.5%,77.2%and 83.7%respectively.The performance of model 4 was better than model 1,2 and 3.Based on PLS model 1 and refine PLS model 4,the multi-objective design spaces were developed which meets CQAs of tableting by dry granulation.Z74 Sophorae Flavescentis Radix and Z80 Menthae Haplocalycis Herba were selected as the research objects,18 representative excipients were selected as candidate excipients,and the binary formulation with drug loading≥ 70%and ternary formulation with 70%drug loading were simulated.The combination of excipients and tablet compression forces in accordance with the predetermined design space(TS≥2 MPa,0.8 ≤SF ≤0.9)was selected to conduct the tableting by dry granulation experiments.The reliability of the formulation design method was proved.Based on the above three parts of research,this paper systematically studied the changes of tabletability in the process of dry granulation by the material library method,and constructed a set of formulation intelligent design methodology of tableting by dry granulation based on the materials properties and compression behavior of raw materials and excipients of TCM.Through this study,it can provide a reference for more scientific screening of excipients in formulation in tableting by dry granulation process of TCM,and provide a basis for the design of dry granulation process of TCM.