Study On Hygroscopic Behavior Of Commonly Used Solid Preparation Excipients And Moisture-proof Technology Of Three Kinds Of Traditional Chinese Medicine Preparations

Object:To determinate the moisture absorption behavior of 28 kinds of commonly used solid preparation materials,optimize the moisture-proof excipients and granulation process of three traditional Chinese medicine preparations of Compound Banlangen Liyan Granules,Xiaoer Bushen Gubiao Granules,Pingzhi Capsules,compare the effects of the three granulation processes of dry granulation,extrusion granulation,fluidized bed granulation on the pharmaceutical properties of TCM extract granules,provide the basis for the moisture-proof technology of solid preparation of traditional Chinese medicine.Methods:1.The water content of 28 kinds of 44 excipients,28 kinds of preparations containing extractives of 3 kinds of preparations and 21 preparation particles with 3 kinds of granulation processes at 25℃（the same below）6.0%～100.0%RH for 0,24,48,72,96,120 h were determined by static adsorption and weighing method.The average hygroscopic rate was calculated every 24 h,and the hygroscopic equilibrium was considered when the average hygroscopic rate was no more than 0.3 mg·g^-1·h^-1.Using correlation coefficient（R²）,residual sum of squares（RSS）and Akakike information criterion（AIC）as indexes,the mathematical model of hygroscopic kinetic curve at 68.9%RH for 120 h and hygroscopic isotherm curve at6.0%～100.0%RH for 120 h was fitted by Origin Pro8.0 software.2.The area under 120 h hygroscopic isotherm curve（AUHIC）between 6.0%～81.0%RH was used to evaluate the hygroscopicity of the samples.The two sides of the hygroscopic isotherm curve for 120 h at 6.0%～100.0%RH were fitted by a straight line,and the critical relative humidity（CRH）was taken as the abscissor of the intersection point of the two lines.The limited relative humidity（LRH）of excipients,granules and capsules was predicted according to the water limit of"Chinese Pharmacopoeia".3.The particle size distribution,specific surface area,pore volume,pore radius,angle of repose,pile density and other pharmacy performance parameters of 21 preparation granules were determined according to the corresponding method in Chinese Pharmacopoeia.Results:1.44 excipients,28 extractives containing excipients,21 preparation granules:the initial water content is 0.07%～13.16%,0.74%～2.60%and 1.44%～4.48%,respectively.120 h water content under 6.0%～100.0%RH were 0.00%～54.42%,0.15%～47.52%and 0.58%～48.36%,respectively.2.Within 6.0%～81.0%RH 120 h,the hygroscopic equilibrium of 43 excipients except povidone K30 was observed.Except for dry,extruded and fluidized Xiaoer Sucrose Granules and Fluidized Pingzhi Hydroxypropylmethylcellulose E6 Granules,the remaining 17 granules were hygroscopic equilibrium.Within 100.0%RH 120 h,18 excipients were hygroscopic balanced,while the other 26 were hygroscopic unbalanced.All the 21 granules were hygroscopically unbalanced at 92.5%RH and 100.0%RH for 120 h.3.Optimal model of hygroscopic dynamic curve for 120 h at 68.9%RH:44 excipients were SWEIBULL2（16）,SWEIBULL1（12）,first-order process（9）,double index（4）and conic curve（3）.28 extracts containing excipients were SWEIBULL2（16）,double index（9）and SWEIBULL1（3）.21 granules were SWEIBULL2（11）,double index（6）,and SWEIBULL1（4）.The common model for all samples is Weibull distribution.The optimal model of hygroscopic isothermal curves of all samples at 6.0%～100.0%RH for 120 h was Peleg equation.4.Optimized moisture-proof pelletizing process routes by AUHIC are as follows:Compound Banlangen Liyan Granules and Xiaoer Bushen Gubiao Granules were both fluidized bed or dry granulated with lactose as excipient.Pingzhi Capsules is dry or extruded pelletized with glyceryl henyl acid as excipient or dry pelletized with anhydrous calcium hydrogen phosphate as excipient.5.The LRH of 44 excipients and 21 preparation granules were 1.6%～100.0%and40.2%～68.9%,respectively.6.The CRH of 32 excipients ranged from 40.6%RH to 94.4%RH,and 12 excipients had no CRH.The CRH of Compound Banlangen Liyan Granules,Xiaoer Bushen Gubiao Granules and Pingzhi Capsules containing extractite powder were 65.8%～68.8%,64.6%～68.7%,66.1%～68.7%,respectively.The CRH of the prepared particles were 69.7%～71.5%,65.2%～71.1%and 65.5%～66.9%,respectively.7.The reduction rates of AUHIC of the three granulation processes for TCM preparation particles were:the extruded Liyan dextrin b Granules 7.06%,fluidized Liyan lactose b Granules 25.00%,dry Xiaoer sucrose Granules 11.47%,fluidized Xiaoer lactose b Granules 16.16%,fluidized Pingzhi hydroxypropyl methyl cellulose E6 b Granules 6.11%,dry fluidized Pingzhi anhydrous calcium phosphate b Granules 4.23%,dry fluidized Pingzhi lipharyndlactose b Granules 6.51%.It can be seen that the three granulation processes have different effects on the hygroscopicity of the three preparation particles,indicating that the hygroscopicity of the three preparation particles is related to the hygroscopicity of the extract powder and excipients and the granulation process.8.The average particle size（90.0～381.5μm）of the 21 particles obtained by the three kinds of granulation processes was in the order of extrusion>fluidized>dry method,the particle size span（1.9～2.9）and the bulk density(0.29～0.74 g·m L^-1)were dry>extruded>fluidized,the specific surface area(0.03～1.19 m²·g^-1)and Angle of rerest（26.28～40.41°）were dry>fluidized>extrusion,the pore volume(0.26～8.46μL·g^-1)and pore radius（8.79～60.91nm）had no obvious correlation with the granulation process.Conclusion:In this paper,the hygroscopic behavior of the granules obtained by three kinds of granulation processes,including water content variation law,hygroscopic equilibrium time,hygroscopicdynamiccurvemodel,hygroscopicisothermcurve model,AUHIC,LRH,CRH,etc.,and the moisture-resistant excipients and the granulation process of the three preparations were optimized.It provides reference for the research on the moisture-proof technology of traditional Chinese medicine preparation.In this paper,AUHIC digital characterization and evaluation of material hygroscopicity are established.According to the hygroscopic isotherm curve,the maximum LRH of the product packaging environment must be predicted according to the moisture limit of"Chinese Pharmacopoeia".LRH is more accurate and objective than CRH to guide the selection of drug packaging materials.It provides basis for the selection of moisture-proof excipients,moisture-proof granulation technology,inner packing materials and relative humidity of storage and transportation of solid preparations of traditional Chinese medicine.